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Grafelman EM, Côté BE, Vlach L, Geise E, Padula GN, Wheeler DS, Hearing MC, Mantsch JR, Wheeler RA. Aversion-induced dopamine reductions predict drug-taking and escape behaviors. Neuropsychopharmacology 2025:10.1038/s41386-025-02101-7. [PMID: 40205012 DOI: 10.1038/s41386-025-02101-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 03/30/2025] [Accepted: 04/01/2025] [Indexed: 04/11/2025]
Abstract
Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured during an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted the performance of escape behavior. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and is generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.
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Affiliation(s)
- Elaine M Grafelman
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA
| | - Bridgitte E Côté
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA
| | - Lisa Vlach
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA
| | - Ella Geise
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA
| | - G Nino Padula
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA
| | - Daniel S Wheeler
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA
| | - Matthew C Hearing
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA
| | - John R Mantsch
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Robert A Wheeler
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
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Hynes T, Bowden-Jones H, Chamberlain S, Belin D. A roadmap for transformative translational research on gambling disorder in the UK. Neurosci Biobehav Rev 2025; 171:106071. [PMID: 39988286 DOI: 10.1016/j.neubiorev.2025.106071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 01/28/2025] [Accepted: 02/18/2025] [Indexed: 02/25/2025]
Abstract
The UK has one of the highest rates of recreational gambling in the world. Some vulnerable individuals progressively lose control over gambling and develop at-risk gambling or gambling disorder (GD), characterised by the compulsive pursuit of gambling. GD destroys lives and incurs massive costs to societies, yet only a few treatments are available. Failure to develop a wider range of interventions is in part due to a lack of funding that has slowed progress in the translational research necessary to understand the individual vulnerability to switch from controlled to compulsive gambling. Current preclinical models of GD do not operationalise the key clinical features of the human condition. The so-called "gambling tasks" for non-human mammals almost exclusively assess probabilistic decision-making, which is not real-world gambling. While they have provided insights into the psychological and neural mechanisms involved in the processing of gains and losses, these tasks have failed to capture those underlying real-world gambling and its compulsive manifestation in humans. Here, we highlight the strengths and weaknesses of current gambling-like behaviour tasks and suggest how their translational validity may be improved. We then propose a theoretical framework, the incentive habit theory of GD, which may prove useful for the operationalisation of the biobehavioural mechanisms of GD in preclinical models. We conclude with a list of recommendations for the development of next-generation preclinical models of GD and discuss how modern techniques in animal behavioural experimentation can be deployed in the context of GD preclinical research to bolster the translational pipeline.
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Affiliation(s)
- Tristan Hynes
- Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK.
| | - Henrietta Bowden-Jones
- Department of Psychiatry, University of Cambridge, UK; National Problem Gambling Clinic & National Centre for Gaming Disorders, London, UK; Department of Brain Sciences, University College London, London, UK
| | - Samuel Chamberlain
- Department of Psychiatry, Faculty of Medicine, University of Southampton, UK; NHS Southern Gambling Service, and NHS Specialist Clinic for Impulsive-Compulsive Conditions, Hampshire and Isle of Wight Healthcare NHS Foundation Trust, Southampton, UK
| | - David Belin
- Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK.
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Templeton-Jager TJ, Diarra S, Kelley LK, Gilpin NW. Systemic bupropion treatment reduces long-access cocaine self-administration in male and female rats. J Psychopharmacol 2025; 39:282-294. [PMID: 39881654 DOI: 10.1177/02698811241312680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
BACKGROUND More than 1 million people in the United States meet the criteria for cocaine use disorder (CUD), and over 19,000 people died from cocaine-related overdoses in 2020, but there are currently no FDA-approved medications for the treatment of CUD. Bupropion is an antidepressant currently prescribed to treat depression and nicotine addiction that acts by inhibiting norepinephrine and dopamine transporters. METHODS In this study, we tested the effect of several doses of systemic bupropion on cocaine self-administration in male and female Wistar rats. In our first experiment, rats self-administered cocaine solution intravenously and were pretreated with systemic bupropion before self-administration sessions. In our second experiment, rats were pre-treated with bupropion before completing tests of locomotor activity and anxiety-like behavior. RESULTS We found that high doses of systemically administered bupropion (60 mg/kg) attenuated cocaine self-administration in male and female rats during extended-access (6 h) sessions. We also found that the highest dose (60 mg/kg) of systemic bupropion was more efficacious in females relative to males during the first hour of operant sessions. Systemic bupropion did not alter locomotor activity, inactive lever presses, or food intake. The Estrous cycle did not influence cocaine intake with or without bupropion. CONCLUSION Our finding that bupropion attenuates cocaine self-administration suggests that bupropion may have promise for reducing cocaine use in humans.
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Affiliation(s)
- Taylor J Templeton-Jager
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Southeast Louisiana VA Healthcare System, New Orleans, LA, USA
| | - Siga Diarra
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Southeast Louisiana VA Healthcare System, New Orleans, LA, USA
| | - Leslie K Kelley
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Southeast Louisiana VA Healthcare System, New Orleans, LA, USA
| | - Nicholas W Gilpin
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Southeast Louisiana VA Healthcare System, New Orleans, LA, USA
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Racine SE, Trolio V, Miller AE, Mehak A, Bicaker E, Wilson S, Benning SD. Testing a Reward-Processing Model of Negative Urgency in Women With and Without Binge Eating. Clin Psychol Sci 2025; 13:407-424. [PMID: 40093918 PMCID: PMC11906250 DOI: 10.1177/21677026241267996] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 04/16/2024] [Indexed: 03/19/2025]
Abstract
Negative urgency (i.e., the tendency to act impulsively when experiencing negative affect) is robustly associated with psychopathology, but the mechanisms underlying negative urgency and its relation to mental health are not well understood. In addition to interfering with cognitive control, negative emotions may lead to impulsive behavior by enhancing reward processing of desired stimuli. In this study, we tested an emotion-enhanced reward-processing model of negative urgency in 153 women who spanned the spectrum of binge-eating severity. Participants completed two experimental tasks under both stressful- and relaxed-mood conditions while physiological, behavioral, and self-report indices of reward processing of palatable food were assessed. Contrary to hypotheses, reward processing of food was not heightened when stressed versus relaxed either in the full sample or in participants with greater negative urgency or binge-eating frequency/severity. Findings are discussed considering study limitations and previous mechanistic work on negative urgency.
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Moses TE, Lenz D, Lundahl LH, Mischel NA, Rabinak C, Greenwald MK. Left ventromedial prefrontal cortex inhibitory rTMS as an anti-stress intervention in opioid use disorder: Trial design. Contemp Clin Trials Commun 2025; 43:101414. [PMID: 39802663 PMCID: PMC11719330 DOI: 10.1016/j.conctc.2024.101414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/12/2024] [Accepted: 12/10/2024] [Indexed: 01/16/2025] Open
Abstract
Background In people with substance use disorders (SUDs), stress-exposure can impair executive function, and increase craving and likelihood of drug-use recurrence. Research shows that acute stressors increase drug-seeking behavior; however, mechanisms underlying this effect are incompletely understood. The Competing Neurobehavioral Decisions System theory posits that persons with SUDs may have hyperactive limbic reward circuitry and hypoactive executive control circuitry. Objective To investigate how inhibitory repetitive transcranial magnetic stimulation (rTMS) targeting the left ventromedial prefrontal cortex (vmPFC) may alter stress-induced executive dysfunction, emotion dysregulation, and drug-seeking in people with opioid use disorder. Methods We will examine effects of a psychological stressor combined with inhibitory (1Hz) left vmPFC rTMS in participants (N = 24) receiving opioid agonist treatment. Participants undergo guided imagery of autobiographical stressors paired with 10 sessions of active vmPFC rTMS vs. sham (within-subject randomized crossover). Stress-induced dysfunction will be indexed with cognitive (e.g., executive function), affective (e.g., emotional arousal), and behavioral (e.g., opioid-seeking) measures pre- and post-rTMS. To confirm changes are associated with altered neural activity in targeted regions, we will measure event-related potentials during key tasks using EEG. We hypothesize that stressors will increase executive dysfunction, emotion dysregulation, and drug-seeking, and that left vmPFC inhibitory rTMS will decrease limbic activation, which could translate to reduced craving and drug-seeking. Conclusion Our findings should offer insights into how neural networks modulate drug-seeking and associated dysfunctions in people with SUDs. The results of this and similar studies can advance theory and neuromodulation interventions for people with SUDs.
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Affiliation(s)
- Tabitha E. Moses
- Dept. of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Danielle Lenz
- Dept. of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Leslie H. Lundahl
- Dept. of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Nicholas A. Mischel
- Dept. of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Christine Rabinak
- Dept. of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, USA
- Dept. of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
| | - Mark K. Greenwald
- Dept. of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, USA
- Dept. of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
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Hinds NM, Wojtas ID, Pulley DM, McDonald SJ, Spencer CD, Sudarikov M, Hubbard NE, Kulick-Soper CM, de Guzman S, Hayden S, Debski JJ, Patel B, Fox DP, Manvich DF. Fos expression in the periaqueductal gray, but not the ventromedial hypothalamus, is correlated with psychosocial stress-induced cocaine-seeking behavior in rats. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.22.634146. [PMID: 39896664 PMCID: PMC11785129 DOI: 10.1101/2025.01.22.634146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Psychosocial stressors are known to promote cocaine craving and relapse in humans but are infrequently employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not been thoroughly explored. Using Fos expression analyses, we sought to examine whether the ventromedial hypothalamus (VMH) or periaqueductal gray (PAG), two critical components of the brain's hypothalamic defense system, are activated during psychosocial stress-induced cocaine seeking. Adult male and female rats self-administered cocaine (0.5 mg/kg/inf IV, fixed-ratio 1 schedule, 2 h/session) over 20 sessions. On sessions 11, 14, 17, and 20, a tactile cue was present in the operant chamber that signaled impending social defeat stress (n=16, 8/sex), footshock stress (n=12, 6/sex), or a no-stress control condition (n=12, 6/sex) immediately after the session's conclusion. Responding was subsequently extinguished, and rats were tested for reinstatement of cocaine seeking during re-exposure to the tactile cue that signaled their impending stress/no-stress post-session event. All experimental groups displayed significant reinstatement of cocaine seeking, but Fos analyses indicated that neural activity within the rostrolateral PAG (rPAGl) was selectively correlated with cocaine-seeking magnitude in the socially-defeated rats. rPAGl activation was also associated with active-defense coping behaviors during social defeat encounters and with Fos expression in prelimbic prefrontal cortex and orexin-negative cells of the lateral hypothalamus/perifornical area in males, but not females. These findings suggest a potentially novel role for the rPAGl in psychosocial stress-induced cocaine seeking, perhaps in a sex-dependent manner.
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Affiliation(s)
- Nicole M. Hinds
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Ireneusz D. Wojtas
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Desta M. Pulley
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Stephany J. McDonald
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Colton D. Spencer
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Milena Sudarikov
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Nicole E. Hubbard
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Colin M. Kulick-Soper
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Samantha de Guzman
- College of Liberal Arts, Temple University, 1114 West Berks Street, Philadelphia, PA 19122
| | - Sara Hayden
- College of Liberal Arts, Temple University, 1114 West Berks Street, Philadelphia, PA 19122
| | - Jessica J. Debski
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Bianca Patel
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Douglas P. Fox
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
| | - Daniel F. Manvich
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Osteopathic Medicine, 42 East Laurel Road, Suite 2200, Stratford, NJ 08084
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Sakmar E, Wemm S, Fogelman N, Hermes G, Sinha R, Milivojevic V. Pregnenolone Reduces Provoked Craving and Cocaine Use in Men and Women with Cocaine Use Disorder: A Pilot Trial. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.07.25320141. [PMID: 39830237 PMCID: PMC11741489 DOI: 10.1101/2025.01.07.25320141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Aim Chronic cocaine use is associated with decreases in neuroactive steroid levels. These adaptations may contribute to continued cocaine use and high relapse risk in individuals with cocaine use disorder (CUD). Thus, this pilot study assessed chronic treatment with 2 supraphysiologic doses of the neuroactive steroid precursor pregnenolone (PREG, 300 mg/day; 500 mg/day) to boost endogenous neuroactive steroid levels and assess its impact on provoked craving and cocaine use outcomes in an 8-week trial in men and women with CUD. Methods Fifty-five treatment-seeking individuals with CUD were randomly assigned to receive either placebo (PLA; n=18; 12M/6F), 300mg PREG/day (n=20; 15M/5F) or 500mg PREG/day (n=17; 12M/5F) for 8 weeks, along with outpatient weekly relapse prevention treatment. Plasma was collected at weeks 2, 5 and 7 to assess circulating pregnenolone levels. A subset of subjects participated in a 3-day experimental component of guided imagery exposure to stress, cocaine cue and neutral conditions in about week 2 of the trial to assess craving response. Cocaine use outcomes was also assessed over the 8-week treatment period. Intent-to-treat analyses were conducted using linear mixed effects models. Results There were no differences between treatment groups on demographic variables and baseline cocaine use. Plasma pregnenolone levels were higher in the 300mg and 500mg PREG groups compared to PLA ( p's < 0.032). Participant trial completion rates were 100% for PLA, 90% for 300mg and 94% for 500mg PREG groups. Placebo group had increased craving in response to stress ( p < .001) and cocaine cue ( p < .001) provocation, whereas the PREG groups showed no increased in provoked cocaine craving. For cocaine use outcomes during the 8-week trial, a significant main effect of treatment group ( p = .005) on the weekly amounts of cocaine use showed e significantly lower amounts used in the 300mg PREG compared to the 500mg PREG group ( p = 0.01) and to PLA ( p = .047). There was also a trend for a treatment group main effect for days of cocaine used (p<.12). Conclusions These pilot findings suggest that supraphysiologic neuroactive steroid PREG doses reduces cocaine craving and may also improve cocaine use outcomes in treatment seeking individuals with CUD. Findings support further assessment and development of PREG in the treatment of CUD.
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Nie Y, Pan T, He J, Li Y. Blunted neural response to real-life social reward anticipation in internet gaming disorder: An event-related potential study. Int J Psychophysiol 2025; 207:112479. [PMID: 39637947 DOI: 10.1016/j.ijpsycho.2024.112479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 11/23/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
Recent research indicates that individuals with Internet gaming disorder (IGD) exhibit impaired social reward processing, evidenced by reduced neural sensitivity to real-life social reward. The aim of the present study is to further investigate the impaired processing of social reward anticipation and reward consumption in individuals with IGD, and explore the relationship between these two components. Using a social incentive delay task with game-related and real-life versions, combined with event-related potential (ERP) technology, we examined 25 individuals with IGD and 25 matched healthy game players. The results showed that, at the behavioral level, individuals with IGD showed significantly slower reaction times to real-life target stimuli compared with game-related target stimuli, which is not observed in healthy controls. At the neural level, the Cue-P3 elicited by real-life incentive cues in individuals with IGD was significantly smaller than that elicited by game-related incentive cues. However, these effects were no longer significant after adding depression and anxiety scores as covariates. There was no significant difference in reward positivity (RewP) elicited between the two types of reward consumption. Furthermore, individuals with IGD showed a positive correlation between Cue-P3 elicited by game-related social incentive cue and RewP elicited by game-related social reward. However, this effect was not observed in the healthy controls. In conclusion, the present study suggests that the blunted allocation of motivated neural attention resources to real-life social incentive cues in individuals with IGD may be the key mechanism underlying their impaired social reward processing. This impairment may be influenced by the higher levels of depression and anxiety symptoms commonly observed in individuals with IGD.
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Affiliation(s)
- Yufeng Nie
- Institute of Psychology and Behavior, Henan University, Jinming Avenue, Kaifeng, Henan Province, China; Key Laboratory of Adolescent Cyberpsychology and Behavior(CCNU), Ministry of Education, Wuhan 430079, China; Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan 430079, China
| | - Ting Pan
- Key Laboratory of Adolescent Cyberpsychology and Behavior(CCNU), Ministry of Education, Wuhan 430079, China; Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan 430079, China
| | - Jinbo He
- Key Laboratory of Adolescent Cyberpsychology and Behavior(CCNU), Ministry of Education, Wuhan 430079, China; Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan 430079, China.
| | - Yongxin Li
- Institute of Psychology and Behavior, Henan University, Jinming Avenue, Kaifeng, Henan Province, China.
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Schick MR, Kiluk BD, Nich C, LaPaglia D, Haeny AM. Measurement invariance of the Perceived Stress Scale across race, sex, and time, and differential impacts on cocaine use treatment outcomes. JOURNAL OF SUBSTANCE USE AND ADDICTION TREATMENT 2024; 166:209493. [PMID: 39151798 PMCID: PMC11392621 DOI: 10.1016/j.josat.2024.209493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/25/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
INTRODUCTION To understand the influence of phenotypic characteristics, such as stress, on substance use treatment outcomes, measures must function equivalently across groups to allow for interpretable comparisons of effects. The present study evaluated measurement invariance of the Perceived Stress Scale (PSS) across race, sex, and time, examined its association with cocaine use disorder (CUD) treatment outcomes, and tested whether associations were moderated by race and/or sex. METHODS Data from four clinical trials evaluating behavioral and/or pharmacological treatments for cocaine use were combined providing a total sample of 302 participants with DSM-IV cocaine abuse/dependence (57.6 % Black, 42.4 % White, 43.7 % females, Mage = 40.22 years, SD = 9.26). RESULTS Factor analyses support a two-factor model (i.e., general stress, self-efficacy to cope with stressors) that demonstrated configural, metric, and scalar invariance across race and sex and configural and metric invariance across time. End-of-treatment stress and coping were both related to treatment outcomes, but not treatment retention. Interactions between baseline and end-of-treatment stress and coping self-efficacy with race and sex predicting treatment retention and outcomes were not significant. CONCLUSIONS Results support the utility of the PSS to examine between-group differences among individuals with CUD and suggest that sociodemographic groups differ in the extent to which stress and self-efficacy to cope influence treatment outcomes.
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Affiliation(s)
- Melissa R Schick
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06511, United States of America.
| | - Brian D Kiluk
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06511, United States of America
| | - Charla Nich
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06511, United States of America
| | - Donna LaPaglia
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06511, United States of America
| | - Angela M Haeny
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06511, United States of America
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Sassover E, Kushnir T, Weinstein AM. Investigating mood-modification, withdrawal, and sensitization in compulsive sexual behaviour. Front Psychiatry 2024; 15:1421028. [PMID: 39465047 PMCID: PMC11502338 DOI: 10.3389/fpsyt.2024.1421028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 09/18/2024] [Indexed: 10/29/2024] Open
Abstract
Background and aims Compulsive Sexual Behaviour (CSB), defined as a persistent failure to control repetitive sexual impulses, has been discussed as a pathological phenomenon for centuries. Various terms, such as excessive sexual behaviour, hyper-sexuality, compulsive sexual behaviour disorder (CSBD), or sexual addiction (SA), have been used to describe it, contributing to ongoing debates about its theoretical framework. The following three studies aim to empirically assess whether CSB exhibits key elements of behavioural addiction (mood-modification, sensitization/tolerance, and withdrawal). Method Three studies, involving participants with and without CSB, were conducted. The mood-modification hypothesis was tested by exposing participants to short films inducing positive, negative, and emotionally neutral moods, followed by an evaluation of their craving for pornography. To test the sensitization hypothesis, participants viewed short films with varying levels of explicit sexual stimuli, and their level of actual wanting and liking were assessed through self-reports. For the withdrawal hypothesis, participants underwent a 10-day sexual abstinence, with self-reports of various symptoms, collected on pre-intervention, 3rd, 7th, and 10th days. Results Contrary to previous studies of addiction, CSB participants didn't show increased craving to mood induction and negative mood actually decreased craving for pornography. Secondly, they showed wanting to explicit sexual stimuli although it was not increased with explicitness. Finally, they demonstrated reduced withdrawal symptom during abstinence. Conclusion The results of this study provide conflicting results concerning the model of behavioural addiction. There is supporting evidence for wanting in response to explicit pornography stimuli although it was not associated with increased explicitness. There is also evidence for reduced withdrawal during abstinence. Finally, there was no evidence that mood modification increases craving for pornography, negative mood actually decreased craving. Further research is needed to test the various models of CSB.
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Grafelman EM, Côté BE, Vlach L, Geise E, Padula GN, Wheeler DS, Hearing M, Mantsch J, Wheeler RA. Aversion-induced drug taking and escape behavior involve similar nucleus accumbens core dopamine signaling signatures. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.05.606651. [PMID: 39149329 PMCID: PMC11326185 DOI: 10.1101/2024.08.05.606651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured in an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted escape attempts. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.
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Affiliation(s)
- Elaine M Grafelman
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA
| | - Bridgitte E Côté
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226
| | - Lisa Vlach
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA
| | - Ella Geise
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA
| | - G Nino Padula
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA
| | - Daniel S Wheeler
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA
| | - Matthew Hearing
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA
| | - John Mantsch
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226
| | - Robert A Wheeler
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA
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12
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Haeny AM, Schick MR, McKenley C, Chowdhary A, Bellamy CD, O'Malley SS, Sinha R. Evidence that personalized racial stress procedures elicit a stress response and increases alcohol craving among Black adults with alcohol use disorder: A laboratory pilot study. Drug Alcohol Depend 2024; 260:111312. [PMID: 38749311 PMCID: PMC11991899 DOI: 10.1016/j.drugalcdep.2024.111312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND The objective of this study was to pilot test newly developed personalized imagery procedures to investigate the impact of racial stress on alcohol craving and emotional and physiological response in Black adults with alcohol use disorder (AUD). METHODS Twenty Black adults (45% women, meanage=37.05, SDage=13.19) with AUD participated in two sessions. In the first, participants described a stressful personal event involving their race and a neutral relaxing situation and these descriptions were used to develop scripts for the subsequent laboratory exposure session. The second session was an experimental provocation session in which participants reported on alcohol craving and emotional response before and after imagined exposure to stress and neutral conditions using personalized racial stress and neutral/relaxing scripts. Conditions were randomized and counterbalanced across subjects, and heart rate and blood pressure were assessed before and after each image. RESULTS Alcohol craving and negative emotions significantly increased, and positive emotions decreased following the racial stress script relative to the neutral/relaxing script. We found no differences in physiological response. Exploratory analyses found that increase in alcohol craving was correlated with racial identity exploration but not racial identity commitment, men reported greater reductions in anger than women in the neutral condition only, and income was correlated with fear in the racial stress condition only. CONCLUSIONS This study provides evidence that personalized racial stress procedures elicit a stress response and increases alcohol craving and emotional response but not physiological response among Black adults with AUD. These findings warrant replication in a larger study.
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Affiliation(s)
- Angela M Haeny
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Racial Equity and Addiction Lab at Yale, New Haven, CT 06519, USA.
| | - Melissa R Schick
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Racial Equity and Addiction Lab at Yale, New Haven, CT 06519, USA
| | - Claudia McKenley
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Racial Equity and Addiction Lab at Yale, New Haven, CT 06519, USA
| | - Aishwarya Chowdhary
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Racial Equity and Addiction Lab at Yale, New Haven, CT 06519, USA; Yale Stress Center, New Haven, CT 06511, USA
| | - Chyrell D Bellamy
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA
| | | | - Rajita Sinha
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Yale Stress Center, New Haven, CT 06511, USA
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13
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Nie Y, Pan T, He J, Li Y. Impaired social reward processing in individuals with Internet gaming disorder and its relationship with early face perception. Addict Behav 2024; 153:108006. [PMID: 38457987 DOI: 10.1016/j.addbeh.2024.108006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/29/2024] [Accepted: 03/01/2024] [Indexed: 03/10/2024]
Abstract
Previous research has found that individuals with Internet gaming disorder (IGD) show different patterns of social function impairments in game-related and real-life social contexts. Impaired social reward processing may be the underlying mechanism according to the Social Motivation Theory. Thus, in this study, event-related potentials were recorded from 24 individuals with IGD and 24 healthy gamers during a social judgement task. We focused on reward positivity (RewP) elicited by game-related and real-life social rewards, and N170 elicited by game avatar faces and real faces. These indicators were used to explore the neurocognitive mechanism of impaired social reward processing in individuals with IGD and its relationship with early face perception. Results showed that (1) the RewP elicited by real-life social reward was considerably reduced in individuals with IGD relative to healthy gamers. (2) The N170 elicited by game avatar faces in individuals with IGD was larger than that elicited by real faces. However, the N170 was not associated with RewP in either group. (3) The score for IGD severity was correlated with the RewP elicited by real-life social reward and the N170 elicited by game avatar face. In conclusion, the present study suggests that the impaired social reward processing in individuals with IGD is mainly manifested in a decreased neural sensitivity to real-life social reward. Meanwhile, the reduced RewP elicited by real-life social reward and the enhanced N170 elicited by game avatar face might serve as potential biomarkers for IGD.
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Affiliation(s)
- Yufeng Nie
- Institute of Psychology and Behavior, Henan University, Jinming Avenue, Kaifeng, Henan Province, China; Key Laboratory of Adolescent Cyberpsychology and Behavior of Ministry of Education, School of Psychology, Central China Normal University, Wuhan, China
| | - Ting Pan
- Key Laboratory of Adolescent Cyberpsychology and Behavior of Ministry of Education, School of Psychology, Central China Normal University, Wuhan, China
| | - Jinbo He
- Key Laboratory of Adolescent Cyberpsychology and Behavior of Ministry of Education, School of Psychology, Central China Normal University, Wuhan, China.
| | - Yongxin Li
- Institute of Psychology and Behavior, Henan University, Jinming Avenue, Kaifeng, Henan Province, China.
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14
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Preston TJ, Cougle JR, Schmidt NB, Macatee RJ. Decomposing the late positive potential to cannabis cues in regular cannabis users: A temporal-spatial principal component analysis. Psychophysiology 2024; 61:e14471. [PMID: 37937737 PMCID: PMC11008592 DOI: 10.1111/psyp.14471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 05/06/2023] [Accepted: 08/18/2023] [Indexed: 11/09/2023]
Abstract
Cannabis use disorder (CUD) is increasing in the United States, yet, specific neural mechanisms of CUD are not well understood. Disordered substance use is characterized by heightened drug cue incentive salience, which can be measured using the late positive potential (LPP), an event-related potential (ERP) evoked by motivationally significant stimuli. The drug cue LPP is typically quantified by averaging the slow wave's scalp-recorded amplitude across its entire time course, which may obscure distinct underlying factors with differential predictive validity; however, no study to date has examined this possibility. In a sample of 105 cannabis users, temporo-spatial Principal Component Analysis was used to decompose cannabis cue modulation of the LPP into its underlying factors. Acute stress was also inducted to allow for identification of specific cannabis LPP factors sensitive to stress. Factor associations with CUD severity were also explored. Eight factors showed significantly increased amplitudes to cannabis images relative to neutral images. These factors spanned early (~372 ms), middle (~824 ms), and late (>1000 ms) windows across frontal, central, and parietal-occipital sites. CUD phenotype individual differences were primarily associated with frontal, middle/late latency factor amplitudes. Acute stress effects were limited to one early central and one late frontal factor. Taken together, results suggest that the cannabis LPP can be decomposed into distinct, temporal-spatial factors with differential responsivity to acute stress and CUD phenotype variability. Future individual difference studies examining drug cue modulation of the LPP should consider (1) frontalcentral poolings in addition to conventional central-parietal sites, and (2) later LPP time windows.
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Bellot M, Soria F, López-Arnau R, Gómez-Canela C, Barata C. Daphnia magna an emerging environmental model of neuro and cardiotoxicity of illicit drugs. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 344:123355. [PMID: 38228265 DOI: 10.1016/j.envpol.2024.123355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/10/2023] [Accepted: 01/13/2024] [Indexed: 01/18/2024]
Abstract
Cocaine, methamphetamine, ectasy (3,4-methylenedioxy amphetamine (MDMA)) and ketamine are among the most consumed drugs worldwide causing cognitive, oxidative stress and cardiovascular problems in humans. Residue levels of these drugs and their transformation products may still enter the aquatic environment, where concentrations up to hundreds of ng/L have been measured. In the present work we tested the hypothesis that psychotropic effects and the mode of action of these drugs in D. magna cognitive, oxidative stress and cardiovascular responses are equivalent to those reported in humans and other vertebrate models. Accordingly we expose D. magna juveniles to pharmacological and environmental relevant concentrations. The study was complemented with the measurement of the main neurotransmitters involved in the known mechanisms of action of these drugs in mammals and physiological relevant amino acids. Behavioural cognitive patters clearly differentiate the 3 psychostimulant drugs (methamphetamine, cocaine, MDMA) from the dissociative one ketamine. Psychostimulant drugs at pharmacological doses (10-200 μM), increased basal locomotion activities and responses to light, and decreased habituation to it. Ketamine only increased habituation to light. The four drugs enhanced the production of reactive oxygen species in a concentration related manner, and at moderate concentrations (10-60 μM) increased heartbeats, diminishing them at high doses (200 μM). In chronic exposures to environmental low concentrations (10-1000 ng/L) the four drugs did not affect any of the behavioural responses measured but methamphetamine and cocaine inhibited reproduction at 10 ng/L. Observed effects on neurotransmitters and related metabolites were in concern with reported responses in mammalian and other vertebrate models: cocaine and MDMA enhanced dopamine and serotonin levels, respectively, methamphetamine and MDMA decreased dopamine and octopamine, and all but MDMA decreased 3 MT levels. Drug effects on the concentration of up to 10 amino acids evidence disruptive effects on neurotransmitter synthesis, the urea cycle, lipid metabolism and cardiac function.
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Affiliation(s)
- Marina Bellot
- Department of Analytical and Applied Chemistry, School of Engineering, Institut Químic de Sarrià-Universitat Ramon Llull, Barcelona, Spain
| | - Fernando Soria
- Department of Analytical and Applied Chemistry, School of Engineering, Institut Químic de Sarrià-Universitat Ramon Llull, Barcelona, Spain
| | - Raul López-Arnau
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Institut de Biomedicina IBUB, University of Barcelona, Barcelona, Spain
| | - Cristian Gómez-Canela
- Department of Analytical and Applied Chemistry, School of Engineering, Institut Químic de Sarrià-Universitat Ramon Llull, Barcelona, Spain
| | - Carlos Barata
- Institute for Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona 18, 08034 Barcelona, Spain.
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Psarianos A, Chryssanthopoulos C, Theocharis A, Paparrigopoulos T, Philippou A. Effects of a Two-Month Exercise Training Program on Concurrent Non-Opiate Substance Use in Opioid-Dependent Patients during Substitution Treatment. J Clin Med 2024; 13:941. [PMID: 38398255 PMCID: PMC10888880 DOI: 10.3390/jcm13040941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/14/2024] [Accepted: 01/25/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND This randomized controlled trial aimed to evaluate the effects of a two-month exercise intervention on the concurrent non-opiate substance use (alcohol, cocaine, cannabis, and benzodiazepines) in opioid users during their medication treatment. METHODS Ninety opioid users (41 females) in methadone and buprenorphine medication treatment were randomly divided into four groups: (a) buprenorphine experimental (BEX; n = 26, aged 41.9 ± 6.1 yrs); (b) buprenorphine control (BCON; n = 25, aged 41.9 ± 5.6 yrs); (c) methadone experimental (MEX; n = 20, aged 46.7 ± 6.6 yrs); and (d) methadone control (MCON; n = 19, aged 46.1 ± 7.5 yrs). The experimental groups (BEX and MEX) followed an aerobic exercise training program on a treadmill for 20 min at 70% HRmax, 3 days/week for 8 weeks. Socio-demographic, anthropometric, and clinical characteristics, as well as non-opioid drug use in days and quantity per week, were assessed before and after the intervention period. RESULTS Following the exercise training, the weekly non-opioid substance consumption (days) decreased (p < 0.05) in both exercise groups and was lower in BEX compared to MEX, while no differences were observed (p > 0.05) between the control groups (BCON vs. MCON) or compared to their baseline levels. Similarly, the daily amount of non-opiate substance intake was reduced (p < 0.05) post-training in BEX and MEX, whereas it did not differ (p > 0.05) in BCON and MCON compared to the baseline. CONCLUSIONS The two-month exercise intervention reduced the non-opioid drug use in both the methadone and buprenorphine substitution groups compared to the controls, suggesting that aerobic exercise training may be an effective strategy for treating patients with OUDs.
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Affiliation(s)
- Alexandros Psarianos
- 1st Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.P.); (T.P.)
- Greek Organization Against Drugs (OΚAΝA), 10433 Athens, Greece;
| | - Costas Chryssanthopoulos
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | | | - Thomas Paparrigopoulos
- 1st Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.P.); (T.P.)
| | - Anastassios Philippou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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Haeny AM, Chowdhary A, King J, Sypher I, O'Malley SS, Sinha R. A thematic analysis of stress, substance-cue, and neutral/relaxing events to inform approaches for improving treatment among Black adults who use substances. JOURNAL OF SUBSTANCE USE AND ADDICTION TREATMENT 2024; 156:209184. [PMID: 37866439 DOI: 10.1016/j.josat.2023.209184] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 10/02/2023] [Accepted: 10/04/2023] [Indexed: 10/24/2023]
Abstract
INTRODUCTION To inform approaches for adapting substance use treatment for Black adults, the aim of this study was to thematically analyze the stressors, triggers for substance use, and neutral/relaxing events reported among Black adults who participated in a lab paradigm. METHODS The sample included 36 Black adults (mean age [years] = 37.47, SD = 7.30; 53 % male, 12 (33 %) with alcohol use disorder, 12 (33 %) with cocaine use disorder, and 12 (33 %) healthy controls). All participants provided detailed stimulus and response context information on the most stressful event they experienced in the past year, an event that involved substance use, and a neutral/relaxing event in a structured interview using a scene development questionnaire, and this information was utilized to generate a personalized imagery script for each event using standardized procedures. Thematic analyses identified the key themes reported within scripts. RESULTS Consistent with a prior thematic analysis on a majority White sample, we found the following themes for the stress scripts: Relational (Violation, Loss, Parenting, Betrayal, Isolation vs. support), Environmental (Housing, Legal), and Achievement (Employment, Role in household). However, our analyses also resulted in new stress themes: Relational (Violation-Racial Microaggressions) and Institutional (Time Wasted). The substance use scripts consisted of the following trigger themes: Social (Social Facilitation, Socially-Sanctioned Substance Use Event, Exposure to Substance Use Friends/Associates), Internal (Free Time, Boredom, Thoughts of Using Substance, Frustration, Reward), and Environment (Availability of Substance, Celebration, Party Environment, Food, Hot Day, Money/Payday). The neutral/relaxing scripts themes were: Outdoor Activities (Admiring Nature, People Watching, Observing Surroundings, Enjoying the Sun, Playing in the Sand, Walking), Quiet Activities (Silence/Quiet, Prayer, Reading), and Indoor Activities (Radio, Television, Bath/Shower, Bed/Chair, Observing from a Window). We found sex differences across scripts. CONCLUSIONS The results suggest that Black people experience unique stressors (e.g., institutional and racial stressors) that are important to consider when modifying treatment to improve outcomes among this group. In addition to stressors, this study also identified high-risk situations involving triggers for use. Taken together these findings suggest targets for the tailoring of coping strategies that could be incorporated for the development of culturally relevant behavioral treatment for SUD.
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Affiliation(s)
- Angela M Haeny
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Race Equity and Addiction Lab at Yale, New Haven, New Haven, CT 06519, USA.
| | - Aishwarya Chowdhary
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Yale Stress Center, New Haven, CT 06511, USA
| | - Jaelen King
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Race Equity and Addiction Lab at Yale, New Haven, New Haven, CT 06519, USA
| | - Isaiah Sypher
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Race Equity and Addiction Lab at Yale, New Haven, New Haven, CT 06519, USA
| | | | - Rajita Sinha
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Yale Stress Center, New Haven, CT 06511, USA
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18
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Milivojevic V, Sinha R. Laboratory and Real-World Experimental Approaches to Understanding Alcohol Relapse. Curr Top Behav Neurosci 2023. [PMID: 37985542 DOI: 10.1007/7854_2023_456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Alcohol use disorder is highly prevalent and high risk of relapse remains a significant treatment challenge. Therefore, the utility of human laboratory models of relapse to further the understanding of psychobiological mechanisms that precipitate relapse risk and allow testing of novel interventions could be of benefit in expediting the development of effective treatments to target high relapse risk. Stress is a risk factor for the development of AUD and for relapse, and furthermore, chronic alcohol use leads to adaptations in central and peripheral stress biology. Here, we review our efforts to assess the integrity of these stress pathways in individuals with alcohol use disorder and whether adaptations in these systems play a role in relapse risk. Using validated human laboratory procedures to model two of the most common situations that contribute to relapse risk, namely stress and alcohol cues, we review how such models in the laboratory can predict subsequent relapse, and how we can measure specific identified biobehavioral markers of relapse effectively and ecologically in the real world. Finally, we discuss the significant implications of these findings for the development of novel and effective interventions that target stress dysregulation and craving as risk factors to treatment.
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Affiliation(s)
- Verica Milivojevic
- Department of Psychiatry, The Yale Stress Center, Yale University School of Medicine, New Haven, CT, USA
| | - Rajita Sinha
- Department of Psychiatry, The Yale Stress Center, Yale University School of Medicine, New Haven, CT, USA.
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19
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Hassanshahi A, Janahmadi M, Razavinasab M, Ranjbar H, Hosseinmardi N, Behzadi G, Kohlmeier KA, Ilaghi M, Shabani M. Preventive putative effect of agmatine on cognitive and molecular outcomes in ventral tegmental area of male offspring following physical and psychological prenatal stress. Dev Psychobiol 2023; 65:e22410. [PMID: 37607891 DOI: 10.1002/dev.22410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 06/06/2023] [Accepted: 06/20/2023] [Indexed: 08/24/2023]
Abstract
Prenatal stress (PS) results from a maternal experience of stressful events during pregnancy, which has been associated with an increased risk of behavioral disorders including substance abuse and anxiety in the offspring. PS is known to result in heightened dopamine release in the ventral tegmental area (VTA), in part through the effects of corticotropin-releasing hormone, which directly excites dopaminergic cells. It has recently been suggested that agmatine plays a role in modulating anxiety-like behaviors. In this study, we investigated whether agmatine could reduce negative cognitive outcomes in male mice prenatally exposed to psychological/physical stress, and whether this could be associated with molecular changes in VTA. Agmatine (37.5 mg/kg) was administrated 30 min prior to PS induction in pregnant Swiss mice. Male offspring were evaluated in a series of behavioral and molecular assays. Findings demonstrated that agmatine reduced the impairment in locomotor activity induced by both psychological and physical PS. Agmatine also decreased heightened conditioned place preference to morphine seen in PS offspring. Moreover, agmatine ameliorated the anxiety-like behavior and drug-seeking behavior induced by PS in the male offspring. Molecular effects were seen in VTA as the enhanced brain-derived neurotrophic factor (BDNF) induced by PS in the VTA was reduced by agmatine. Behavioral tests indicate that agmatine exerts a protective effect on PS-induced impairments in male offspring, which could be due in part to agmatine-associated molecular alterations in the VTA. Taken together, our data suggest that prenatal treatment with agmatine exerts protective effect against negative consequences of PS on the development of affective circuits in the offspring.
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Affiliation(s)
- Amin Hassanshahi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahyar Janahmadi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moazamehosadat Razavinasab
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Hoda Ranjbar
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Narges Hosseinmardi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gila Behzadi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kristi A Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mehran Ilaghi
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Shabani
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
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20
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McReynolds JR, Wolf CP, Starck DM, Mathy JC, Schaps R, Krause LA, Hillard CJ, Mantsch JR. Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats. Neuropsychopharmacology 2023; 48:1121-1132. [PMID: 37188846 PMCID: PMC10267161 DOI: 10.1038/s41386-023-01589-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 04/01/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023]
Abstract
Stress is prevalent in the lives of those with substance use disorders (SUDs) and influences SUD outcomes. Understanding the neurobiological mechanisms through which stress promotes drug use is important for the development of effective SUD interventions. We have developed a model wherein exposure to a stressor, uncontrollable electric footshock, daily at the time of cocaine self-administration escalates intake in male rats. Here we test the hypothesis that stress-induced escalation of cocaine self-administration requires the CB1 cannabinoid receptor. Male Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during 2-h sessions comprised of four 30-min self-administration components separated by 5-min shock sequences or 5-min shock-free periods for 14 days. Footshock produced an escalation of cocaine self-administration that persisted following shock removal. Systemic administration of the cannabinoid receptor type 1 (CB1R) antagonist/inverse agonist, AM251, attenuated cocaine intake only in rats with a history of stress. This effect was localized to the mesolimbic system, as intra-nucleus accumbens (NAc) shell and intra-ventral tegmental area (VTA) micro-infusions of AM251 attenuated cocaine intake only in stress-escalated rats. Cocaine self-administration, regardless of stress history, increased CB1R binding site density in the VTA, but not NAc shell. Following extinction, cocaine-primed reinstatement (10 mg/kg, ip) was increased in rats with prior footshock during self-administration. AM251 attenuated reinstatement only in rats with a stress history. Altogether, these data demonstrate that mesolimbic CB1Rs are required to escalate intake and heighten relapse susceptibility and suggest that repeated stress at the time of cocaine use regulates mesolimbic CB1R activity through a currently unknown mechanism.
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Affiliation(s)
- Jayme R McReynolds
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA.
- Department of Pharmacology & Systems Physiology and Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Colten P Wolf
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA
| | - Dylan M Starck
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA
| | - Jacob C Mathy
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA
| | - Rebecca Schaps
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA
| | - Leslie A Krause
- Department of Pharmacology & Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Cecilia J Hillard
- Department of Pharmacology & Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - John R Mantsch
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA
- Department of Pharmacology & Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
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Yue Y, Zou L, Li H, Xia Y, Ren Z, Yang F, Kong D, Re G, Luo H, Zhang Z, Wang K, Zhu M. Therapeutic effect of implanted and non-invasive vagus nerve stimulation on heroin-induced anxiety. Biochem Biophys Res Commun 2023; 652:46-54. [PMID: 36809704 DOI: 10.1016/j.bbrc.2023.02.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/01/2023] [Accepted: 02/15/2023] [Indexed: 02/18/2023]
Abstract
Substance addiction causes anxiety, which in turn reinforces the maintaining of substance use, resulting in a vicious circle. And this circle is one of the reasons why addiction is so hard to cure. However, there is no treatment involved in addiction-induced anxiety at present. We tested whether VNS (vagus nerve stimulation) can improve heroin-induced anxiety, and made a comparison between nVNS (transcervical vagus nerve stimulation) and taVNS (transauricular vagus nerve stimulation) on therapeutic effect. Mice were subjected to nVNS or taVNS before heroin administration. By observing c-Fos expression in the NTS (nucleus of the solitary tract), we assessed vagal fiber activation. Using the OFT (open field test) and the EPM (elevated cross maze test), we evaluated the anxiety-like behaviors of the mice. Using immunofluorescence, we observed the proliferation and activation of microglia in the hippocampus. And ELISA was used to measure the levels of proinflammatory factors in the hippocampus. Both nVNS and taVNS significantly increased the expression of c-Fos in the nucleus of solitary tract, suggesting the feasibility of nVNS and taVNS. The anxiety level of heroin-treated mice was significantly increased, microglia in the hippocampus was significantly proliferated and activated, and the proinflammatory factors (IL-1β, IL-6, TNF-α) in the hippocampus were significantly up-regulated. Crucially, both nVNS and taVNS reversed the above changes caused by heroin addiction. SIGNIFICANCE: It was confirmed that the therapeutic effect of VNS on heroin-induced anxiety may be an effective treatment method to break the "addiction-anxiety" cycle and provides some insights for subsequent treatment of addiction.
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Affiliation(s)
- Yingbiao Yue
- National Health Commission Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650032, China
| | - Lei Zou
- Department of Hepatobiliary Surgery, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
| | - Hong Li
- Narcotics Control Bureau of the Ministry of Public Security of Yunnan Province, Kunming, 650032, China
| | - Yu Xia
- Peking University Health Science Center, Beijing, 100191, China
| | - Zhouyang Ren
- Narcotics Control Bureau of the Ministry of Public Security of Yunnan Province, Kunming, 650032, China
| | - Fazhen Yang
- Narcotics Control Bureau of the Ministry of Public Security of Yunnan Province, Kunming, 650032, China
| | - Deshenyue Kong
- National Health Commission Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650032, China
| | - Guofen Re
- National Health Commission Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650032, China
| | - Huayou Luo
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | | | | | - Mei Zhu
- First Affiliated Hospital of Kunming Medical University, Kunming, China.
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22
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Rosenthal A, Garbusow M, Romanczuk-Seiferth N, Beck A. Effects of a brief mindfulness meditation practice on Pavlovian-to-instrumental transfer in alcohol use disorder - a pilot study. Front Psychiatry 2023; 14:1134458. [PMID: 37168079 PMCID: PMC10164967 DOI: 10.3389/fpsyt.2023.1134458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/04/2023] [Indexed: 05/13/2023] Open
Abstract
Introduction Pavlovian conditioned contextual cues have been suggested to modulate instrumental action and might explain maladaptive behavior such as relapse in participants suffering from alcohol use disorder (AUD). Pavlovian-to-Instrumental transfer (PIT) experimentally assesses the magnitude of this context-dependent effect and studies have shown a larger PIT effect in AUD populations. Taken this into account, a reduction of the influence of cues on behavior seems warranted and one approach that could alter such cue reactivity is mindfulness. Mindfulness-based interventions have been shown to be efficient in the treatment of AUD, but underlying mechanisms are yet to be elucidated. Therefore, we aim at investigating the effect of a brief mindful body scan meditation on the magnitude of the PIT effect in AUD subjects and matched controls. Methods Using a randomized within-subjects design, we compared the effect of a short audio guided body scan meditation against a control condition (audio of nature sounds) on PIT in healthy (n = 35) and AUD (n = 27) participants. Results We found no differences in PIT effect between healthy and AUD participants as well as between conditions. However, a significant interaction effect points to a decreased PIT effect after body scan meditation in AUD subjects only. Discussion These pilot results suggest that AUD might be susceptible to mindfulness-induced changes in PIT, with these findings contributing to entangling the underlying mechanisms of the efficacy of mindfulness-based interventions in AUD. However, further investigation should confirm these preliminary results and the efficacy of mindfulness meditation practice in decreasing the PIT effect.
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Affiliation(s)
- Annika Rosenthal
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Charité – Berlin University of Medicine, Berlin, Germany
- Department of Social and Preventive Medicine, University of Potsdam, Potsdam, Germany
- *Correspondence: Annika Rosenthal,
| | - Maria Garbusow
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Charité – Berlin University of Medicine, Berlin, Germany
| | - Nina Romanczuk-Seiferth
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Charité – Berlin University of Medicine, Berlin, Germany
- Department of Psychology, Clinical Psychology and Psychotherapy, MSB Medical School Berlin, Berlin, Germany
| | - Anne Beck
- Faculty of Health Sciences, Health and Medical University, University of Potsdam, Potsdam, Germany
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23
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Milivojevic V, Sullivan L, Tiber J, Fogelman N, Simpson C, Hermes G, Sinha R. Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder. Psychopharmacology (Berl) 2023; 240:101-114. [PMID: 36445398 PMCID: PMC10630889 DOI: 10.1007/s00213-022-06278-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 11/10/2022] [Indexed: 11/30/2022]
Abstract
RATIONALE Chronic alcohol intake down-regulates GABAergic transmission and reduces levels of neuroactive steroids. These changes are associated with greater stress dysregulation and high alcohol craving which in turn increases relapse risk. OBJECTIVES This study tested whether potentiation of the neurosteroid system with pregnenolone (PREG), a precursor to neuroactive steroids and known to increase GABAergic transmission, will normalize chronic alcohol-related stress adaptations in the hypothalamic-pituitary-adrenal (HPA) axis and autonomic responses and reduce alcohol craving to significantly impact relapse risk. METHODS Forty-three treatment-seeking individuals with alcohol use disorder (AUD) were randomized to placebo (PBO) or supraphysiologic pregnenolone doses of 300 mg or 500 mg treatment using a parallel-between subject design as part of a larger 8-week pilot clinical trial. In week 2, they participated in a 3-day laboratory experiment where on each day they self-administered the assigned study drug in the laboratory and were then exposed to 5-min personalized guided imagery provocation of stress, alcohol, or neutral/relaxing cues, one condition per day on separate days, in a random, counterbalanced order. Repeated assessments of alcohol craving, anxiety, HPA axis, heart rate (HR), systolic (SBP), and diastolic blood pressure (DBP) and serum pregnenolone levels were made on each day. RESULTS Pregnenolone levels were significantly increased in the PREG groups versus PBO. PREG treatment decreased stress- and alcohol cue- induced craving and dose-specifically reduced stress-induced anxiety in the 300 mg/day group. Both PREG doses compared to PBO also normalized CORT/ACTH and increased stress-induced HR, stress- and cue-induced SBP, and in the 300 mg PREG group cue-induced DBP responses relative to neutral condition. CONCLUSIONS Findings indicate that pregnenolone decreases stress- and alcohol cue-provoked craving and normalizes HPA axis and autonomic arousal in individuals with AUD, thereby supporting the need for further assessment of pregnenolone in the treatment of AUD.
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Affiliation(s)
- Verica Milivojevic
- The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06519, USA.
| | - Liam Sullivan
- The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06519, USA
| | - Jessica Tiber
- The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06519, USA
| | - Nia Fogelman
- The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06519, USA
| | - Christine Simpson
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Gretchen Hermes
- The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06519, USA
| | - Rajita Sinha
- The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06519, USA
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24
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Mantsch JR. Corticotropin releasing factor and drug seeking in substance use disorders: Preclinical evidence and translational limitations. ADDICTION NEUROSCIENCE 2022; 4:100038. [PMID: 36531188 PMCID: PMC9757758 DOI: 10.1016/j.addicn.2022.100038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
The neuropeptide, corticotropin releasing factor (CRF), has been an enigmatic target for the development of medications aimed at treating stress-related disorders. Despite a large body of evidence from preclinical studies in rodents demonstrating that CRF receptor antagonists prevent stressor-induced drug seeking, medications targeting the CRF-R1 have failed in clinical trials. Here, we provide an overview of the abundant findings from preclinical rodent studies suggesting that CRF signaling is involved in stressor-induced relapse. The scientific literature that has defined the receptors, mechanisms and neurocircuits through which CRF contributes to stressor-induced reinstatement of drug seeking following self-administration and conditioned place preference in rodents is reviewed. Evidence that CRF signaling is recruited with repeated drug use in a manner that heightens susceptibility to stressor-induced drug seeking in rodents is presented. Factors that may determine the influence of CRF signaling in substance use disorders, including developmental windows, biological sex, and genetics are examined. Finally, we discuss the translational failure of medications targeting CRF signaling as interventions for substance use disorders and other stress-related conditions. We conclude that new perspectives and research directions are needed to unravel the mysterious role of CRF in substance use disorders.
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Affiliation(s)
- John R Mantsch
- Department of Pharmacology & Toxicology, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226, United States
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25
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Milivojevic V, Charron L, Fogelman N, Hermes G, Sinha R. Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder. Biomolecules 2022; 12:biom12111593. [PMID: 36358943 PMCID: PMC9687893 DOI: 10.3390/biom12111593] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic cocaine use leads to adaptations in stress biology and in neuroactive steroid system. These adaptations are associated with high cocaine craving and increased relapse risk. This study tested whether potentiation of the neuroactive steroid system with the precursor pregnenolone (PREG) affects stress- and cue-induced cocaine craving, anxiety and autonomic response in individuals with cocaine use disorder (CUD). Thirty treatment-seeking individuals (21 Male, 9 Female) with CUD were randomized to placebo (PBO) or supraphysiologic PREG doses of 300 mg or 500 mg per day for 8 weeks. After 2 weeks of treatment, participants were exposed to 5-min personalized guided imagery provocation of stress, cocaine, or neutral/relaxing cues in a 3-day experiment, one condition per day on separate days, in a random, counterbalanced order. Repeated assessment of cocaine craving, anxiety, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) were assessed on each day. PREG significantly increased pregnenolone levels compared to PBO. Both PREG doses decreased stress- and cocaine cue-induced craving and reduced both stress- and cue-induced anxiety only in the 500 mg/day group. The 500 mg/day PREG group also displayed decreased stress-induced HR, SBP and DBP. Findings indicate that pregnenolone decreases stress- and cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.
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26
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Vamvakopoulou IA, Fonville L, Hayes A, McGonigle J, Elliott R, Ersche KD, Flechais R, Orban C, Murphy A, Smith DG, Suckling J, Taylor EM, Deakin B, Robbins TW, Nutt DJ, Lingford-Hughes AR, Paterson LM. Selective D3 receptor antagonism modulates neural response during negative emotional processing in substance dependence. Front Psychiatry 2022; 13:998844. [PMID: 36339857 PMCID: PMC9627287 DOI: 10.3389/fpsyt.2022.998844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction Negative affective states contribute to the chronic-relapsing nature of addiction. Mesolimbic dopamine D3 receptors are well placed to modulate emotion and are dysregulated in substance dependence. Selective antagonists might restore dopaminergic hypofunction, thus representing a potential treatment target. We investigated the effects of selective D3 antagonist, GSK598809, on the neural response to negative emotional processing in substance dependent individuals and healthy controls. Methodology Functional MRI BOLD response was assessed during an evocative image task, 2 h following acute administration of GSK598809 (60 mg) or placebo in a multi-site, double-blind, pseudo-randomised, cross-over design. Abstinent drug dependent individuals (DD, n = 36) comprising alcohol-only (AO, n = 19) and cocaine-alcohol polydrug (PD, n = 17) groups, and matched controls (n = 32) were presented with aversive and neutral images in a block design (contrast of interest: aversive > neutral). Whole-brain mixed-effects and a priori ROI analyses tested for group and drug effects, with identical models exploring subgroup effects. Results No group differences in task-related BOLD signal were identified between DD and controls. However, subgroup analysis revealed greater amygdala/insular BOLD signal in PD compared with AO groups. Following drug administration, GSK598809 increased BOLD response across HC and DD groups in thalamus, caudate, putamen, and pallidum, and reduced BOLD response in insular and opercular cortices relative to placebo. Multivariate analyses in a priori ROIs revealed differential effects of D3 antagonism according to subgroup in substantia nigra; GSK598809 increased BOLD response in AO and decreased response in PD groups. Conclusion Acute GSK598809 modulates the BOLD response to aversive image processing, providing evidence that D3 antagonism may impact emotional regulation. Enhanced BOLD response within D3-rich mesolimbic regions is consistent with its pharmacology and with attenuation of substance-related hypodopaminergic function. However, the lack of group differences in task-related BOLD response and the non-specific effect of GSK598809 between groups makes it difficult to ascertain whether D3 antagonism is likely to be normalising or restorative in our abstinent populations. The suggestion of differential D3 modulation between AO and PD subgroups is intriguing, raising the possibility of divergent treatment responses. Further study is needed to determine whether D3 antagonism should be recommended as a treatment target in substance dependence.
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Affiliation(s)
- Ioanna A. Vamvakopoulou
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Leon Fonville
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Alexandra Hayes
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - John McGonigle
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Rebecca Elliott
- Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, The University of Manchester, Manchester, United Kingdom
| | - Karen D. Ersche
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Remy Flechais
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Csaba Orban
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Anna Murphy
- Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, The University of Manchester, Manchester, United Kingdom
| | - Dana G. Smith
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom
| | - John Suckling
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Eleanor M. Taylor
- Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, The University of Manchester, Manchester, United Kingdom
| | - Bill Deakin
- Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, The University of Manchester, Manchester, United Kingdom
| | - Trevor W. Robbins
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom
| | - David J. Nutt
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Anne R. Lingford-Hughes
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Louise M. Paterson
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, United Kingdom
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27
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Kexel AK, Kluwe-Schiavon B, Baumgartner MR, Engeli EJE, Visentini M, Kirschbaum C, Seifritz E, Ditzen B, Soravia LM, Quednow BB. Cue-induced cocaine craving enhances psychosocial stress and vice versa in chronic cocaine users. Transl Psychiatry 2022; 12:443. [PMID: 36220809 PMCID: PMC9554190 DOI: 10.1038/s41398-022-02204-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 09/16/2022] [Accepted: 09/23/2022] [Indexed: 11/30/2022] Open
Abstract
Stress and craving, it has been found, contribute to the development and maintenance of and relapse in cocaine use disorder. Chronic cocaine users (CU), previous research has shown, display altered physiological responses to psychosocial stress and increased vegetative responding to substance-related cues. However, how psychosocial stress and cue-induced craving interact in relation to the CU's physiological responses remains largely unknown. We thus investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. In a crossed and balanced design, the participants were randomly exposed to a video-based cocaine-cue paradigm and the Trier Social Stress Test (TSST) or vice versa to investigate possible mutually augmenting effects of both stressors on physiological stress responses. Over the course of the experimental procedure, plasma cortisol, ACTH, noradrenaline, subjective stress, and craving were assessed repeatedly. To estimate the responses during the cocaine-cue paradigm and TSST, growth models and discontinuous growth models were used. Overall, though both groups did not differ in their endocrinological responses to the TSST, CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU, but when the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. In CU, cocaine-cues robustly evoked craving but no physiological stress response, while cue-induced craving was intensified after the TSST. Taken together, though CU did not show an altered acute stress response during the TSST, stress and craving together seemed to have mutually augmenting effects on their stress response.
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Affiliation(s)
- Ann-Kathrin Kexel
- Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital, University of Zurich, Lenggstrasse 31, 8032, Zurich, Switzerland.
| | - Bruno Kluwe-Schiavon
- Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital, University of Zurich, Lenggstrasse 31, 8032, Zurich, Switzerland
- Cognition in Context, Research Center for Psychological Science, University of Lisbon, Alameda da Universidade, 1649-013, Lisbon, Portugal
| | - Markus R Baumgartner
- Centre for Forensic Hair Analytics, Institute of Forensic Medicine, University of Zurich, Kurvenstrasse 17, 8006, Zurich, Switzerland
| | - Etna J E Engeli
- Centre for Addictive Disorders, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital, University of Zurich, Selnaustrasse 9, 8001, Zurich, Switzerland
| | - Monika Visentini
- Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital, University of Zurich, Lenggstrasse 31, 8032, Zurich, Switzerland
| | - Clemens Kirschbaum
- Department of Biopsychology, Technical University Dresden, Zellescher Weg 19, 01069, Dresden, Germany
| | - Erich Seifritz
- Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital, University of Zurich, Lenggstrasse 31, 8032, Zurich, Switzerland
- Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland
| | - Beate Ditzen
- Institute for Medical Psychology, Heidelberg University Hospital, Heidelberg, Germany
- Ruprecht-Karls University Heidelberg, Bergheimer Str. 20, 69115, Heidelberg, Germany
| | - Leila M Soravia
- Translational Research Center, University Hospital of Psychiatry, University of Bern, Bolligenstrasse 111, 3000, Bern 60, Switzerland
| | - Boris B Quednow
- Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital, University of Zurich, Lenggstrasse 31, 8032, Zurich, Switzerland.
- Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
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28
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Meredith LR, Green R, Grodin EN, Chorpita M, Miotto K, Ray LA. Ibudilast moderates the effect of mood on alcohol craving during stress exposure. Exp Clin Psychopharmacol 2022; 30:620-631. [PMID: 36102596 PMCID: PMC9484034 DOI: 10.1037/pha0000458] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Neuroinflammation is implicated in the development and maintenance of alcohol use disorder (AUD) and neuroimmune therapeutics show promise in treating AUD. Proinflammatory signaling contributes to progressive elevations in the dysfunction of mood and alcohol craving. The current study sought to examine potential biobehavioral mechanisms of neuroimmune modulation in AUD under experimental conditions. In a community sample of individuals with AUD who completed a placebo-controlled crossover trial of ibudilast, we tested the effect of ibudilast on the relationship between mood states and alcohol craving. Multilevel modeling analyses tested the hypothesis that ibudilast would moderate the effect of positive and negative mood states on alcohol craving during stress and cue exposures. Results revealed that after stress-induction, participants' feelings of depression and happiness were more strongly predictive of their craving for alcohol while taking ibudilast as compared with placebo (ps < .03). These results suggest that with neuroimmune modulation, positive and negative mood states may have a stronger influence on one's desire to drink, such that craving may be more mood dependent. No moderating effect of ibudilast on mood states and craving were observed after alcohol cue exposure. Given the potential of anti-inflammatory treatments to reduce depressive symptomatology, this strengthened relationship between mood and craving under ibudilast might reduce the likelihood of stress-related craving and subsequent drinking over time. Moreover, ibudilast may enhance the benefits of happiness, such that maintaining positive mood in the face of acute stress may attenuate craving. Future trials directly testing the clinical implications of these mechanistic findings are warranted. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Affiliation(s)
| | - ReJoyce Green
- Department of Psychology, University of California, Los Angeles, CA, USA
| | - Erica N. Grodin
- Department of Psychology, University of California, Los Angeles, CA, USA
| | - Marie Chorpita
- Department of Psychology, University of California, Los Angeles, CA, USA
| | - Karen Miotto
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA
| | - Lara A. Ray
- Department of Psychology, University of California, Los Angeles, CA, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA
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29
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Aldridge GM, Zarin TA, Brandner AJ, George O, Gilpin NW, Repunte-Canonigo V, Sanna PP, Koob GF, Vendruscolo LF, Schmeichel BE. Effects of single and dual hypocretin-receptor blockade or knockdown of hypocretin projections to the central amygdala on alcohol drinking in dependent male rats. ADDICTION NEUROSCIENCE 2022; 3:100028. [PMID: 35965958 PMCID: PMC9365098 DOI: 10.1016/j.addicn.2022.100028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Hypocretin/Orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral-mediated targeting of HCRT to determine participation in compulsive alcohol drinking and measured HCRT-receptor mRNA expression in the extended amygdala of both alcohol-dependent and non-dependent male rats. Rats were made dependent through chronic intermittent exposure to alcohol vapor and were tested for the acute effect of HCRT-R1-selective (SB-408124; SB-R1), HCRT-R2-selective (NBI-80713; NB-R2), or dual HCRT-R1/2 (NBI-87571; NB-R1/2) antagonism on alcohol intake. NB-R2 and NB-R1/2 antagonists each dose-dependently decreased overall alcohol drinking in alcohol-dependent rats, whereas, SB-R1 decreased alcohol drinking in both alcohol-dependent and non-dependent rats at the highest dose (30 mg/kg). SB-R1, NB-R2, and NB-R1/2 treatment did not significantly affect water drinking in either alcohol-dependent or non-dependent rats. Additional PCR analyses revealed a significant decrease in Hcrtr1 mRNA expression within the central amygdala (CeA) of dependent rats under acute withdrawal conditions compared to nondependent rats. Lastly, a shRNA-encoding adeno-associated viral vector with retrograde function was used to knockdown HCRT in CeA-projecting neurons from the lateral hypothalamus (LH). LH-CeA HCRT knockdown significantly attenuated alcohol self-administration in alcohol-dependent rats. These observations suggest that HCRT signaling in the CeA is necessary for alcohol-seeking behavior during dependence. Together, these data highlight a role for both HCRT-R1 and -R2 in dependent alcohol-seeking behavior.
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Affiliation(s)
- Gabriel M. Aldridge
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Tyler A. Zarin
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Adam J. Brandner
- Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Olivier George
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
- Department of Psychiatry, School of Medicine, University of California, San Diego, San Diego, CA, USA
| | - Nicholas W. Gilpin
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Vez Repunte-Canonigo
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, United States
| | - Pietro P. Sanna
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, United States
| | - George F. Koob
- Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
| | - Leandro F. Vendruscolo
- Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
| | - Brooke E. Schmeichel
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
- Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
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Hormonal milieu drives economic demand for cocaine in female rats. Neuropsychopharmacology 2022; 47:1484-1492. [PMID: 35338254 PMCID: PMC9205886 DOI: 10.1038/s41386-022-01304-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 01/21/2023]
Abstract
There are substantial sex differences in drug abuse, and a key feature of cocaine addiction is pathologically high motivation for drug. We investigated the role of ovarian hormones on cocaine demand in female rats using a within-session threshold behavioral economics (BE) procedure, which allows us to compare motivation for drug across hormonal states and sex while controlling for differences in dose and intake. This approach quantifies demand elasticity (α) and free consumption (Q0, consumption at null effort) to determine motivation for cocaine. Overall, female rats showed greater motivation for cocaine compared to males. However, this difference was cycle phase-dependent - motivation for cocaine when females were in proestrus was lower compared to the same animals across cycle phases, and overall similar to that of males. Hormonal cycle phase accounted for 70% of the within-subject variance in demand elasticity, obscuring other individual differences in female demand. High serum progesterone (P4; e.g., in proestrus) predicted decreased cocaine motivation (high demand elasticity), whereas serum estradiol (E2) correlated to greater intake at null effort (Q0). However, individual differences were revealed across OVX females, who displayed a range of demand elasticity, as seen in males. E2 replacement in OVX females increased motivation for cocaine, whereas P4 replacement decreased motivation. We also found that as few as 4 weeks of cocaine self-administration accelerated estropause in female rats as young as 12 weeks old. By 13 weeks of self-administration, proestrus epochs were no longer observed, and cocaine demand was potentiated by persistent estrus in all females. Thus, P4 signaling is a key modulator of cocaine demand in females that may underlie previously observed sex differences in addiction phenotypes.
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Fouyssac M, Peña-Oliver Y, Puaud M, Lim NTY, Giuliano C, Everitt BJ, Belin D. Negative Urgency Exacerbates Relapse to Cocaine Seeking After Abstinence. Biol Psychiatry 2022; 91:1051-1060. [PMID: 34922736 DOI: 10.1016/j.biopsych.2021.10.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/21/2021] [Accepted: 10/08/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND The mechanisms through which drug-cue-induced negative affective states are involved in relapse have not been defined. We tested the hypothesis that in individuals having developed a dorsolateral striatum (DLS)-dependent cue-controlled cocaine-seeking habit, the loss of the opportunity to enact the drug-seeking response during abstinence results in an urge to act that exacerbates relapse severity mediated by negative urgency. METHODS Eighty-seven male Sprague Dawley rats were trained to seek cocaine under the influence of the conditioned reinforcing properties of drug-paired cues or not. We investigated whether the tendency to relapse depended on the aversive state of withdrawal or instead on the loss of opportunity to perform the ingrained drug-seeking response after periods of abstinence. The striatal locus of control over cocaine seeking at baseline and relapse was investigated using in situ hybridization of the cellular activity marker C-fos and assessment of the sensitivity of instrumental drug seeking to dopamine receptor blockade in the dorsomedial striatum-dependent goal-directed and DLS-dependent habit systems. RESULTS The development of a DLS-dependent cue-controlled cocaine-seeking habit prior to abstinence resulted in a marked increase in drug seeking at relapse, which was not motivated by a cocaine withdrawal state and was no longer dependent on the DLS habit system. Instead, it reflected the emergence of negative urgency caused by the prevention of the performance of the habit during abstinence and underpinned by transient engagement of the goal-directed system. CONCLUSIONS These results show that ingrained cue-controlled drug-seeking habits increase the pressure to relapse.
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Affiliation(s)
- Maxime Fouyssac
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom
| | - Yolanda Peña-Oliver
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom
| | - Mickaёl Puaud
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom
| | - Nicole T Y Lim
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom
| | - Chiara Giuliano
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom
| | - Barry J Everitt
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom
| | - David Belin
- Department of Psychology, University of Cambridge, Cambridge, United Kingdom.
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Stark R, Markert C, Kruse O, Walter B, Strahler J, Klein S. Individual cortisol response to acute stress influences neural processing of sexual cues. J Behav Addict 2022; 11:506-519. [PMID: 35895611 PMCID: PMC9295234 DOI: 10.1556/2006.2022.00037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/28/2022] [Accepted: 04/28/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND AND AIMS Problematic pornography use can be conceptualized as an impulse control disorder or alternatively as a behavioral addiction. Stress is an important trigger in addiction, but less is known about the neural effect of stress in problematic pornography use. Therefore, we aimed at investigating the effect of stress during the anticipation and viewing of sexually explicit material while considering person characteristics related to potentially being at risk for developing problematic pornography use. METHODS In an fMRI study (n = 157 men, age: mean = 25.46, SD = 4.11) we used a sexual incentive delay task. A social stress test was used to induce stress in half of the participants. Salivary cortisol was repeatedly measured and person characteristics were considered moderating the effects of cortisol response. RESULTS We found no group differences in the neural responses during the anticipation phase, but a higher reactivity to sexual stimuli in the dACC in the stress group. Acute stress activated a pronounced cortisol response, which positively correlated with neural activations in the reward system (NAcc, dACC) to sexual cues. Further, the individual time spent on pornography use moderated the effect of cortisol in some regions of the reward system (dACC, mOFC). DISCUSSION AND CONCLUSIONS Our results suggest that acute stress related increases in cortisol can enhance the incentive value of cues announcing sexual stimuli. This might explain why acute stress is considered a trigger of pornography use and relapse and why individual stress response might be a risk factor for developing a problematic pornography use.
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Affiliation(s)
- Rudolf Stark
- Department of Psychotherapy and Systems Neuroscience, Justus Liebig University of Giessen, Germany,Bender Institute of Neuroimaging, Justus Liebig University of Giessen, Germany,Center of Mind, Brain and Behavior, Universities of Marburg and Giessen, Germany,Corresponding author. E-mail:
| | - Charlotte Markert
- Department of Psychotherapy and Systems Neuroscience, Justus Liebig University of Giessen, Germany,Bender Institute of Neuroimaging, Justus Liebig University of Giessen, Germany,Center of Mind, Brain and Behavior, Universities of Marburg and Giessen, Germany
| | - Onno Kruse
- Department of Psychotherapy and Systems Neuroscience, Justus Liebig University of Giessen, Germany,Bender Institute of Neuroimaging, Justus Liebig University of Giessen, Germany
| | - Bertram Walter
- Department of Psychotherapy and Systems Neuroscience, Justus Liebig University of Giessen, Germany,Center of Mind, Brain and Behavior, Universities of Marburg and Giessen, Germany
| | - Jana Strahler
- Sportpsychology, Institute of Sport and Sport Sciences, University of Freiburg, Germany
| | - Sanja Klein
- Department of Psychotherapy and Systems Neuroscience, Justus Liebig University of Giessen, Germany,Bender Institute of Neuroimaging, Justus Liebig University of Giessen, Germany,Center of Mind, Brain and Behavior, Universities of Marburg and Giessen, Germany
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Alessi MC, Martinotti G, De Berardis D, Sociali A, Di Natale C, Sepede G, Cheffo DPR, Monti L, Casella P, Pettorruso M, Sensi S, Di Giannantonio M. Craving variations in patients with substance use disorder and gambling during COVID-19 lockdown: The Italian experience. World J Clin Cases 2022; 10:882-890. [PMID: 35127903 PMCID: PMC8790460 DOI: 10.12998/wjcc.v10.i3.882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/18/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Following the development of the coronavirus disease-2019 (COVID-19) pandemic in Italy, a strict lockdown was imposed from March 9 to May 5, 2020. The risks of self-medication through alcohol or psychoactive substance abuse were increased, as well as the tendency to adopt pathological behaviors, such as gambling and internet addiction.
AIM To evaluate the impact of the COVID-19 pandemic and associated containment measures on craving in a group of patients suffering from substance use disorder and/or gambling disorder who were in treatment in outpatient units or in residency programs as inpatients.
METHODS One hundred and fifty-three patients completed a structured questionnaire evaluating craving and other behaviors using a visual analogue scale (VAS). Forty-one subjects completed a pencil and paper questionnaire during the interview. The clinician provided an online questionnaire to 112 patients who had virtual assessments due to lockdown restrictions. Statistical analyses were performed using Statistica version 8.0. Quantitative parameters are presented as the mean ± SD and qualitative parameters as number and percentage per class. The Kolmogorov-Smirnov test was used to check for normality of distributions. Analysis of variance and Duncan post hoc test were employed to analyze differences among subgroup means. The associations between variables were measured using Pearson's correlation. A P value of < 0.05 was considered significant.
RESULTS The variation in craving between the present and the month before showed VAS-related reductions of craving in 57%, increases in 24%, and no significant change in 19% of the sample. The level of craving was significantly higher (F = 4.36; P < 0.05) in outpatients (n = 97; mean = 3.8 ± 3.1) living in their own home during the quarantine compared with inpatients (n = 56; mean = 2.8 ± 2.8) in residential programs. Craving for tetrahydrocannabinol was the greatest (4.94, P < 0.001) among various preferred substances.
CONCLUSION The unexpected result of this study may be explained by a perceived lack of availability of substances and gambling areas and/or decreased social pressure on a subject usually excluded and stigmatized, or the acquisition of a new social identity based on feelings of a shared common danger and fate that overshadowed the sense of exclusion and rejection in the abuser.
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Affiliation(s)
- Maria Chiara Alessi
- Department of Neuroscience, Imaging, Clinical Sciences, University G. d'Annunzio, Chieti-Pescara 66100, Italy
| | - Giovanni Martinotti
- Department of Neuroscience, Imaging, Clinical Sciences, University G. d'Annunzio, Chieti-Pescara 66100, Italy
- Department of Pharmacy, Pharmacology, Clinical Sciences, University of Hertfordshire, Hertfordshire AL10 9AB, United Kingdom
| | | | - Antonella Sociali
- Department of Neuroscience, Imaging, Clinical Sciences, University G. d'Annunzio, Chieti-Pescara 66100, Italy
| | - Chiara Di Natale
- Department of Neuroscience, Imaging, Clinical Sciences, University G. d'Annunzio, Chieti-Pescara 66100, Italy
| | - Gianna Sepede
- Department of Neuroscience, Imaging, Clinical Sciences, University G. d'Annunzio, Chieti-Pescara 66100, Italy
| | - Daniela Pia Rosaria Cheffo
- Department of Mental Health, UOS Psicologia Ospedaliera Fondazione Policlinico Gemelli IRCSS, Rome 00118, Italy
| | - Laura Monti
- Department of Mental Health, UOS Psicologia Ospedaliera Fondazione Policlinico Gemelli IRCSS, Rome 00118, Italy
| | - Pietro Casella
- Department of Mental Health and Addiction Services, ASL Roma 1, Rome 00118, Italy
| | - Mauro Pettorruso
- Department of Neuroscience, Imaging, Clinical Sciences, University G. d'Annunzio, Chieti-Pescara 66100, Italy
| | - Stefano Sensi
- Department of Neuroscience, Imaging, Clinical Sciences, University G. d'Annunzio, Chieti-Pescara 66100, Italy
| | - Massimo Di Giannantonio
- Department of Neuroscience, Imaging, Clinical Sciences, University G. d'Annunzio, Chieti-Pescara 66100, Italy
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Xu S, Zhang K, Luo T. Development of the Risk of Relapse Assessment Scale for methamphetamine abusers in China. Drug Alcohol Depend 2021; 227:108992. [PMID: 34482042 DOI: 10.1016/j.drugalcdep.2021.108992] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/16/2021] [Accepted: 07/31/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Relapse to Methamphetamine (MA) use is among the public concerns nowadays, which result in adverse outcomes associated with physical and mental health problems. This study aimed to develop the Risk of Relapse Assessment Scale (RRAS) for Chinese MA abusers. METHOD A sample of 438 MA abusers aged between 17 and 58 years (M ± SD age = 34.08 ± 8.61 years) in compulsory detoxification institutes were randomly divided into sub-sample 1 (n = 223) and sub-sample 2 (n = 215) for conducting exploratory factor analysis and confirmatory factor analysis respectively. RESULTS Compared four-factor model with 19 items and three-factor model with 16 items using principal axis factoring, the three-factor solution showed better model fit. Three factors were identified in RRAS: Craving for MA, Social Recognition, and Attitude towards MA which accounted for 50.06 % of the variance in total. The results of confirmation factor analysis demonstrated good model fits (CFI = 0.95; TLI = 0.94; RMSEA = 0.050; GFI = 0.92). The internal consistency analysis indicated that the three-factor model had satisfactory reliability with Cronbach alphas ranging from 0.71 to 0.88 for different factors. Overall, the results showed that the RRAS had good construct validity and satisfactory reliability, suggesting that it was a good instrument for measuring the relapse of MA. CONCLUSIONS The RRAS with good psychometric properties provides a promising future for developing effective relapse prevention programs for MA abusers in China.
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Affiliation(s)
- Shuping Xu
- Department of Social Work, East China University of Political Science & Law, China
| | - Kun Zhang
- Department of Social Work, East China University of Political Science & Law, China
| | - Tingyu Luo
- Department of Social Work and Social Administration, The University of Hong Kong, Hong Kong.
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Higginbotham JA, Jones NM, Wang R, Christian RJ, Ritchie JL, McLaughlin RJ, Fuchs RA. Basolateral amygdala CB1 receptors gate HPA axis activation and context-cocaine memory strength during reconsolidation. Neuropsychopharmacology 2021; 46:1554-1564. [PMID: 33452429 PMCID: PMC8280224 DOI: 10.1038/s41386-020-00919-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/24/2020] [Accepted: 11/15/2020] [Indexed: 11/09/2022]
Abstract
Re-exposure to a cocaine-associated context triggers craving and relapse through the retrieval of salient context-drug memories. Upon retrieval, context-drug memories become labile and temporarily sensitive to modification before they are reconsolidated into long-term memory stores. The effects of systemic cannabinoid type 1 receptor (CB1R) antagonism indicate that CB1R signaling is necessary for cocaine-memory reconsolidation and associated glutamatergic plasticity in the basolateral amygdala (BLA); however, the contribution of BLA CB1R signaling to cocaine-memory reconsolidation is unknown. Here, we assessed whether intra-BLA CB1R manipulations immediately after cocaine-memory retrieval alter cocaine-memory strength indexed by subsequent drug context-induced cocaine-seeking behavior in an instrumental rodent model of drug relapse. Administration of the CB1R antagonist, AM251 (0.3 µg/hemisphere) into the BLA increased subsequent drug context-induced cocaine-seeking behavior in a memory retrieval-dependent and anatomically selective manner. Conversely, the CB1R agonist, WIN55,212-2 (0.5 or 5 µg/hemisphere) failed to alter this behavior. In follow-up experiments, cocaine-memory retrieval elicited robust hypothalamic-pituitary-adrenal axis activation, as indicated by a rise in serum corticosterone concentrations. Intra-BLA AM251 administration during memory reconsolidation selectively increased this cocaine-memory retrieval-induced corticosterone response. Intra-BLA corticosterone administration (3 or 10 ng/hemisphere) during memory reconsolidation did not augment subsequent cocaine-seeking behavior, suggesting that CB1R-dependent effects of corticosterone on memory strength, if any, are mediated outside of the BLA. Together, these findings suggest that CB1R signaling in the BLA gates cocaine-memory strength, possibly by diminishing the impact of cue-induced arousal on the integrity of the reconsolidating memory trace or on the efficacy of the memory reconsolidation process.
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Affiliation(s)
- Jessica A. Higginbotham
- grid.30064.310000 0001 2157 6568Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA USA
| | - Nicole M. Jones
- grid.30064.310000 0001 2157 6568Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA USA
| | - Rong Wang
- grid.30064.310000 0001 2157 6568Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA USA
| | - Robert J. Christian
- grid.30064.310000 0001 2157 6568Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA USA
| | - Jobe L. Ritchie
- grid.30064.310000 0001 2157 6568Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA USA
| | - Ryan J. McLaughlin
- grid.30064.310000 0001 2157 6568Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA USA ,grid.30064.310000 0001 2157 6568Washington State University Alcohol and Drug Abuse Research Program, Pullman, WA USA ,grid.30064.310000 0001 2157 6568Translational Addiction Research Collaborative, Washington State University, Pullman, WA USA
| | - Rita A. Fuchs
- grid.30064.310000 0001 2157 6568Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA USA ,grid.30064.310000 0001 2157 6568Washington State University Alcohol and Drug Abuse Research Program, Pullman, WA USA ,grid.30064.310000 0001 2157 6568Translational Addiction Research Collaborative, Washington State University, Pullman, WA USA
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Chen C, Zhang KZ, Gong X, Lee MK, Wang YY. Preventing relapse to information technology addiction through weakening reinforcement: A self-regulation perspective. INFORMATION & MANAGEMENT 2021. [DOI: 10.1016/j.im.2021.103485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Zhang S, Zhornitsky S, Wang W, Le TM, Dhingra I, Chen Y, Li CR. Resting state hypothalamic and dorsomedial prefrontal cortical connectivity of the periaqueductal gray in cocaine addiction. Addict Biol 2021; 26:e12989. [PMID: 33300238 DOI: 10.1111/adb.12989] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/16/2020] [Accepted: 10/31/2020] [Indexed: 12/14/2022]
Abstract
Cocaine-dependent (CD) individuals demonstrate significant anxiety and dysphoria during withdrawal, a negative emotional state that may perpetuate drug seeking and consumption. An extensive body of work has focused on characterizing reward circuit dysfunction, but relatively little is known about the pain circuit during cocaine withdrawal. In an earlier study, we highlighted how cue-elicited functional connectivity between the periaqueductal gray (PAG), a subcortical hub of the pain circuit, and ventromedial prefrontal cortex supports tonic craving in recently abstinent CD. The functional organization of the brain can be characterized by intrinsic connectivities, and it is highly likely that the resting state functional connectivity (rsFC) of the PAG may also be altered in association with cocaine use variables. Here, we examined this issue in 52 CD and 52 healthy control (HC) participants. Imaging data were processed with published routines, and the findings were evaluated with a corrected threshold. In a covariance analysis, CD as compared with HC showed higher PAG rsFC with the hypothalamus, dorsomedial prefrontal, and inferior parietal cortices. Further, these connectivities were correlated negatively with tonic cocaine craving and recent cocaine use, respectively. Higher hypothalamic and frontoparietal rsFC with the PAG may reflect a compensatory process to regulate craving and compulsive drug use. The findings provide additional evidence in humans implicating the PAG circuit and may help research of the role of negative reinforcement in sustaining habitual drug use in cocaine addiction.
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Affiliation(s)
- Sheng Zhang
- Department of Psychiatry Yale University School of Medicine New Haven CT USA
| | - Simon Zhornitsky
- Department of Psychiatry Yale University School of Medicine New Haven CT USA
| | - Wuyi Wang
- Department of Psychiatry Yale University School of Medicine New Haven CT USA
| | - Thang M. Le
- Department of Psychiatry Yale University School of Medicine New Haven CT USA
| | - Isha Dhingra
- Department of Psychiatry Yale University School of Medicine New Haven CT USA
| | - Yu Chen
- Department of Psychiatry Yale University School of Medicine New Haven CT USA
| | - Chiang‐shan R. Li
- Department of Psychiatry Yale University School of Medicine New Haven CT USA
- Department of Neuroscience Yale University School of Medicine New Haven CT USA
- Interdepartmental Neuroscience Program Yale University New Haven CT USA
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Zhornitsky S, Le TM, Wang W, Dhingra I, Chen Y, Li CSR, Zhang S. Midcingulate Cortical Activations Interrelate Chronic Craving and Physiological Responses to Negative Emotions in Cocaine Addiction. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2021; 1:37-47. [PMID: 35664438 PMCID: PMC9164547 DOI: 10.1016/j.bpsgos.2021.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Caccamise A, Van Newenhizen E, Mantsch JR. Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking. J Neurochem 2021; 157:1697-1713. [PMID: 33660857 PMCID: PMC8941950 DOI: 10.1111/jnc.15340] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/26/2021] [Accepted: 02/28/2021] [Indexed: 12/12/2022]
Abstract
In individuals with substance use disorders, stress is a critical determinant of relapse susceptibility. In some cases, stressors directly trigger cocaine use. In others, stressors interact with other stimuli to promote drug seeking, thereby setting the stage for relapse. Here, we review the mechanisms and neurocircuitry that mediate stress-triggered and stress-potentiated cocaine seeking. Stressors trigger cocaine seeking by activating noradrenergic projections originating in the lateral tegmentum that innervate the bed nucleus of the stria terminalis to produce beta adrenergic receptor-dependent regulation of neurons that release corticotropin releasing factor (CRF) into the ventral tegmental area (VTA). CRF promotes the activation of VTA dopamine neurons that innervate the prelimbic prefrontal cortex resulting in D1 receptor-dependent excitation of a pathway to the nucleus accumbens core that mediates cocaine seeking. The stage-setting effects of stress require glucocorticoids, which exert rapid non-canonical effects at several sites within the mesocorticolimbic system. In the nucleus accumbens, corticosterone attenuates dopamine clearance via the organic cation transporter 3 to promote dopamine signaling. In the prelimbic cortex, corticosterone mobilizes the endocannabinoid, 2-arachidonoylglycerol (2-AG), which produces CB1 receptor-dependent reductions in inhibitory transmission, thereby increasing excitability of neurons which comprise output pathways responsible for cocaine seeking. Factors that influence the role of stress in cocaine seeking, including prior history of drug use, biological sex, chronic stress/co-morbid stress-related disorders, adolescence, social variables, and genetics are discussed. Better understanding when and how stress contributes to drug seeking should guide the development of more effective interventions, particularly for those whose drug use is stress related.
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Affiliation(s)
- Aaron Caccamise
- Graduate Program in Neuroscience, Marquette University, Milwaukee, WI 53201
| | - Erik Van Newenhizen
- Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226
| | - John R. Mantsch
- Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226
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Fonville L, Paterson L, Herlinger K, Hayes A, Hill R, Nutt D, Lingford-Hughes A. Functional evaluation of NK 1 antagonism on cue reactivity in opiate dependence; An fMRI study. Drug Alcohol Depend 2021; 221:108564. [PMID: 33548897 PMCID: PMC8047866 DOI: 10.1016/j.drugalcdep.2021.108564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/27/2020] [Accepted: 12/28/2020] [Indexed: 10/26/2022]
Abstract
BACKGROUND Opiate addiction is a major health challenge with substantial societal cost. Though harm minimisation strategies have been effective, there is a growing need for new treatments for detoxification and relapse prevention. Preclinical research has found neurokinin 1 (NK1) receptors have prominent effects on opiate reward and reinforcement, and human studies have found NK1 antagonism led to reductions in craving and withdrawal. However, its effect on brain mechanisms in opiate addiction has not yet been examined. METHODS This study aims to assess the impact of NK1 antagonist aprepitant on heroin cue-elicited changes in blood-oxygenation level dependent (BOLD) signal in opiate dependent individuals undergoing detoxification. Participants will attend two scanning sessions and receive a single dose of aprepitant (320 mg) and a placebo in a randomised, cross-over design. During functional magnetic resonance imaging participants will undergo two runs of a cue reactivity task, which consists of passive viewing of drug cues or neutral cues in a block design fashion. We hypothesise that NK1 antagonism will attenuate the BOLD response to drug cues in the caudate nucleus and amygdala. Regions of interest were selected based on NK1 receptor density and their role in cue reactivity and craving.
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Affiliation(s)
- Leon Fonville
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, United Kingdom.
| | - Louise Paterson
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, United Kingdom
| | - Katherine Herlinger
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, United Kingdom
| | - Alexandra Hayes
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, United Kingdom
| | - Raymond Hill
- Department of Metabolism, Digestion and Reproduction, Imperial College London, United Kingdom
| | - David Nutt
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, United Kingdom
| | - Anne Lingford-Hughes
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, United Kingdom
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He J, Pan T, Nie Y, Zheng Y, Chen S. Behavioral modification decreases approach bias in young adults with internet gaming disorder. Addict Behav 2021; 113:106686. [PMID: 33069109 DOI: 10.1016/j.addbeh.2020.106686] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 09/26/2020] [Accepted: 09/26/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND One of the key symptoms of Internet gaming disorder is the impulsive pursuit of Internet games, which causes individuals with this disorder to have a tendency to approach gaming cues. Dual processing theory states that this approach bias is caused by the suppression of reflective processing and the hyperactivity of impulsive processing. Therefore, reverse modification training for approach bias can suppress impulsive processing, thereby reducing or treating the disorder. METHOD In this study, 48 individuals with Internet gaming disorder were selected and randomly assigned to the following two groups: the experimental group and the control group. The 24 participants in the experimental group received a 4-day stimulus-response compatibility (SRC) approach bias modification treatment, whereas the 24 participants in the control group received a corresponding SRC pseudomodification training. RESULTS The approach response time of both groups to the gaming cues was significantly shorter than that to the neutral cues at baseline. After the modification, the response time of the experimental group to the gaming cues significantly increased, whereas the scores for Internet gaming disorder severity, anxiety level and craving significantly decreased. However, the control group subjects did not show these effects. CONCLUSION The current results imply that individuals with Internet gaming disorder show approach bias toward Internet gaming cues, and SRC reverse modification training can significantly correct this bias and therefore have therapeutic effects to some extent.
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Affiliation(s)
- Jinbo He
- Key Laboratory of Adolescent Cyberpsychology and Behavior of Ministry of Education, Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan, China.
| | - Ting Pan
- Key Laboratory of Adolescent Cyberpsychology and Behavior of Ministry of Education, Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan, China
| | - Yufeng Nie
- Key Laboratory of Adolescent Cyberpsychology and Behavior of Ministry of Education, Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan, China
| | - Yang Zheng
- Key Laboratory of Adolescent Cyberpsychology and Behavior of Ministry of Education, Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan, China
| | - Suqing Chen
- Key Laboratory of Adolescent Cyberpsychology and Behavior of Ministry of Education, Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan, China
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Alcohol. Alcohol 2021. [DOI: 10.1016/b978-0-12-816793-9.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Japarin RA, Yusoff NH, Hassan Z, Müller CP, Harun N. Cross-reinstatement of mitragynine and morphine place preference in rats. Behav Brain Res 2020; 399:113021. [PMID: 33227244 DOI: 10.1016/j.bbr.2020.113021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/13/2020] [Accepted: 11/13/2020] [Indexed: 02/08/2023]
Abstract
Kratom is a medicinal plant that exhibits promising results as an opiate substitute. However, there is little information regarding the abuse profile of its main psychoactive constituent, mitragynine (MG), particularly in relapse to drug abuse. Using the place conditioning procedure as a model of relapse, this study aims to evaluate the ability of MG to induce conditioned place preference (CPP) reinstatement in rats. To evaluate the cross-reinstatement effects, MG and morphine were injected to rats that previously extinguished a morphine- or MG-induced CPP. Following a CPP acquisition induced by either MG (10 and 30 mg/kg, i.p.) or morphine (10 mg/kg, i.p.), rats were subjected to repeated CPP extinction sessions. A low dose priming injection of MG or morphine produced a reinstatement of the previously extinguished CPP. In the second experiment of this study, a priming injection of morphine (1, 3 and 10 mg/kg, i.p.) dose-dependently reinstated an MG-induced CPP. Likewise, a priming injection of MG (3, 10 and 30 mg/kg, i.p.) was able to dose-dependently reinstate a morphine-induced CPP. The present study demonstrates a cross-reinstatement effect between MG and morphine, thereby suggesting a similar interaction in their rewarding motivational properties. The findings from this study also suggesting that a priming exposure to kratom and an opioid may cause relapse for a previously abused drug.
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Affiliation(s)
- Rima Atria Japarin
- Centre for Drug Research, Universiti Sains Malaysia, 11800, Gelugor, Penang, Malaysia
| | - Nurul Hasnida Yusoff
- Centre for Drug Research, Universiti Sains Malaysia, 11800, Gelugor, Penang, Malaysia
| | - Zurina Hassan
- Centre for Drug Research, Universiti Sains Malaysia, 11800, Gelugor, Penang, Malaysia
| | - Christian P Müller
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany
| | - Norsyifa Harun
- Centre for Drug Research, Universiti Sains Malaysia, 11800, Gelugor, Penang, Malaysia.
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Zhang S, Zhornitsky S, Wang W, Dhingra I, Le TM, Li CSR. Cue-elicited functional connectivity of the periaqueductal gray and tonic cocaine craving. Drug Alcohol Depend 2020; 216:108240. [PMID: 32853997 PMCID: PMC7606798 DOI: 10.1016/j.drugalcdep.2020.108240] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Withdrawal from chronic cocaine use leads to anxiety and dysphoria that may perpetuate habitual drug use. The pain circuit is widely implicated in the processing and manifestations of negative emotions. Numerous studies have focused on characterizing reward circuit dysfunction but relatively little is known about the pain circuit response during cocaine withdrawal. METHODS Here we examined the activity and connectivity of the periaqueductal gray (PAG), a hub of the pain circuit, during cocaine cue exposure in 52 recently abstinent cocaine dependent participants (CD, 42 men). Imaging data were processed with published routines, and the results were evaluated at a corrected threshold. RESULTS CD showed higher activation of the PAG and connectivity of the PAG with the ventromedial prefrontal cortex (vmPFC) during cocaine as compared to neutral cue exposure. PAG-vmPFC connectivity was positively and negatively correlated with tonic cocaine craving, as assessed by the Cocaine Craving Questionnaire, in male and female CD, respectively, and the sex difference was confirmed by a slope test. Granger causality analyses showed that the PAG Granger caused vmPFC time series in men and the reverse was true in women, substantiating sex differences in the directional interactions of the PAG and vmPFC. CONCLUSION The findings provide the first evidence in humans implicating the PAG circuit in cocaine withdrawal and cocaine craving and advance our understanding of the role of the pain circuit and negative reinforcement in sustaining habitual drug use in cocaine addiction.
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Affiliation(s)
- Sheng Zhang
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
| | - Simon Zhornitsky
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Wuyi Wang
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Isha Dhingra
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Thang M. Le
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT
| | - Chiang-shan R. Li
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT,Department of Neuroscience, Yale University School of Medicine, New Haven, CT,Interdepartmental Neuroscience Program, Yale University, New Haven, CT
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Guerrero-Bautista R, Franco-García A, Hidalgo JM, Fernández-Gómez F, Milanés MV, Núñez C. Blockade of D3 receptor prevents changes in DAT and D3R expression in the mesolimbic dopaminergic circuit produced by social stress- and cocaine prime-induced reinstatement of cocaine-CPP. J Psychopharmacol 2020; 34:1300-1315. [PMID: 32648812 DOI: 10.1177/0269881120936468] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Cocaine may cause persistent changes in the brain, which are more apparent in DA transporter (DAT) and DA receptor availability within the nucleus accumbens (NAc). On the other hand, the DA D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for substance use disorders. AIMS This study aims to assess the impact of selective D3R antagonism on DAT and D3R after reinstatement of cocaine preference (CPP) induced by an acute session of social defeat stress (SDS) and a cocaine prime in mice after a period of abstinence. METHODS Male mice were conditioned with 25 mg/kg of cocaine for 4 days. After 60 days of extinction training mice were pretreated with the selective D3R antagonist SB-277011A before the re-exposure to a priming dose of cocaine or to a single SDS session. CPP scores were determined and levels of DAT, D3R, phospho Akt (pAkt) and phospho mTOR (pmTOR) were assessed in the NAc shell. RESULTS An increase in DAT and D3R expression was seen in the NAc after both a cocaine prime- and SDS-induced reinstatement of CPP. Pretreatment with SB-277011A blocked elevated DAT and D3R expression as well as SDS-induced reinstatement. By contrast, the blockade of D3R did not modified the cocaine prime-induced CPP. Changes in DAT and D3R expression do not seem to occur via the canonic pathway involving Akt/mTOR. CONCLUSIONS Our results suggest that the selective D3R antagonist ability to inhibit DAT and D3R up-regulation could represent a possible mechanism for its behavioral effects in cocaine-memories reinstatement induced by social stress.
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Affiliation(s)
- Rocío Guerrero-Bautista
- Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, Murcia, Spain.,Murcia Research Institute of Health Sciences (IMIB), Avda. Buenavista, Murcia, Spain
| | - Aurelio Franco-García
- Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, Murcia, Spain.,Murcia Research Institute of Health Sciences (IMIB), Avda. Buenavista, Murcia, Spain
| | - Juana M Hidalgo
- Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, Murcia, Spain.,Murcia Research Institute of Health Sciences (IMIB), Avda. Buenavista, Murcia, Spain
| | - Francisco Fernández-Gómez
- Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, Murcia, Spain.,Murcia Research Institute of Health Sciences (IMIB), Avda. Buenavista, Murcia, Spain
| | - M Victoria Milanés
- Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, Murcia, Spain.,Murcia Research Institute of Health Sciences (IMIB), Avda. Buenavista, Murcia, Spain
| | - Cristina Núñez
- Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, Murcia, Spain.,Murcia Research Institute of Health Sciences (IMIB), Avda. Buenavista, Murcia, Spain
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McHugh RK, Nguyen MD, Fitzmaurice GM, Dillon DG. Behavioral strategies to reduce stress reactivity in opioid use disorder: Study design. Health Psychol 2020; 39:806-814. [PMID: 32833482 DOI: 10.1037/hea0000862] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVES More than 2 million people in the United States had an opioid use disorder in 2017. Treatment for opioid use disorder-particularly medication combined with psychosocial support-is effective for reducing opioid use and decreasing overdose risk. However, approximately 50% of people who receive treatment will relapse or drop out. Stress reactivity, defined as the subjective and physiological response to stress, is heightened in people with opioid use disorder and higher stress reactivity is associated with poorer outcomes. Preliminary studies suggest that stress reactivity may be a key mechanistic target for improving outcomes. This article describes the design of an ongoing study examining behavioral strategies for reducing stress reactivity in adults with opioid use disorder. Our objective is to test the efficacy of two behavioral strategies for reducing stress reactivity and enhancing behavioral persistence in the context of stress (distress tolerance). METHOD We will recruit 120 adults with opioid use disorder and randomly assign them to brief training in (a) cognitive reappraisal, (b) affect labeling, or (c) a psychoeducational control. Participants will receive the training intervention followed by a laboratory stressor during which they will be instructed to apply the trained skill. RESULTS Subjective and physiological responses to stress will be measured as indices of stress reactivity and the stressor task will include a behavioral persistence component as a measure of distress tolerance. CONCLUSIONS The ultimate goal of this study is to inform the development of behavioral interventions that can be used as an adjunct to medication-based treatment for opioid use disorder. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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Affiliation(s)
| | | | | | - Daniel G Dillon
- Center for Depression Anxiety and Stress Research, McLean Hospital
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Hyperexcitability of VTA dopaminergic neurons in male offspring exposed to physical or psychological prenatal stress. Prog Neuropsychopharmacol Biol Psychiatry 2020; 101:109923. [PMID: 32173457 DOI: 10.1016/j.pnpbp.2020.109923] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 02/02/2023]
Abstract
Prenatal stress (PS) exposure leads to cognitive and behavioral alterations in offspring including an increased risk of substance abuse and anxiety disorders. Signalling from dopamine (DA) neurons of the ventral tegmental area (VTA) in the mesoaccumbal and mesocortical pathways plays a vital role in drug dependency and anxiety behavior. To provide further knowledge about the changes in drug seeking behavior and anxiety behaviors in prenatally stressed mice, we conducted ex vivo investigations in VTA brain slices of adult male PS offspring to evaluate the effects of two types of PS (physical vs. psychological) on activity of DA neurons. Elevated plus maze (EPM) was used to assess anxiety-like behaviors and conditioned place preference (CPP) was used to evaluate drug reinforcing effects in mice. An increased anxiety-like behavior and preference to morphine was observed in prenatally stressed mice. PS VTA DA cells exhibited greater Ih current and a higher frequency and amplitude of sEPSCs, which were consistent with a greater degree of pre- or postsynaptic excitability of the VTA. This was confirmed by lower rheobase and lower firing thresholds in PS VTA neurons, as well as increases in spontaneous firing frequency. When taken together, these data suggest that alterations in VTA DA neurons in this mouse model of prenatal stress might be associated with later life alterations in drug seeking and anxiety-like behaviors through their role in mesocortical and mesoaccumbal pathways.
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Sherman BJ, Baker NL, Brady KT, Joseph JE, Nunn LM, McRae-Clark A. The effect of oxytocin, gender, and ovarian hormones on stress reactivity in individuals with cocaine use disorder. Psychopharmacology (Berl) 2020; 237:2031-2042. [PMID: 32388622 PMCID: PMC8210538 DOI: 10.1007/s00213-020-05516-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 04/01/2020] [Indexed: 12/22/2022]
Abstract
RATIONALE Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction. OBJECTIVES To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response. METHODS One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min. RESULTS Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033). CONCLUSIONS Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.
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Affiliation(s)
- Brian J Sherman
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 125 Doughty Street, Suite 190, Charleston, SC, 29425, USA.
| | - Nathaniel L Baker
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Kathleen T Brady
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 125 Doughty Street, Suite 190, Charleston, SC, 29425, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC, USA
| | - Jane E Joseph
- Department of Neuroscience, Medical University of South Carolina, Charleston, USA
| | - Lisa M Nunn
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 125 Doughty Street, Suite 190, Charleston, SC, 29425, USA
| | - Aimee McRae-Clark
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 125 Doughty Street, Suite 190, Charleston, SC, 29425, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC, USA
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Winstanley EL, Mahoney JJ, Lander LR, Berry JH, Marshalek P, Zheng W, Haut MW. Something to despair: Gender differences in adverse childhood experiences among rural patients. J Subst Abuse Treat 2020; 116:108056. [PMID: 32741501 DOI: 10.1016/j.jsat.2020.108056] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 05/18/2020] [Accepted: 05/31/2020] [Indexed: 01/27/2023]
Abstract
Existing research has demonstrated that patients in treatment for an opioid use disorder (OUD) have high rates of adverse childhood experiences (ACE) compared to community-based samples. While research has documented important gender differences in ACEs in patients with OUD receiving treatment in urban areas, research has not shown whether these findings would generalize to rural and Appalachian areas, which are known to have lower ACE scores. We conducted a secondary analysis of existing clinical data, utilizing intake assessment data from a rural Appalachian outpatient buprenorphine program. We restricted the sample to patients with an OUD who presented for treatment between June 2018 and June 2019 (n = 173). The clinical intake assessment included a modified 17-item ACE instrument that patients self-administered. More than half (54.3%) of patients reported having experienced 4+ categories of adverse childhood experiences. On average, females endorsed 4.5 categories of adverse experiences, whereas males endorsed 3.3 (p < 0.00); female patients were significantly more likely to have experienced sexual abuse (42.4% versus 10.6%, p < 0.00). Alarmingly, 25.9% of females and 8.2% of males reported being forced to have sex before age 18. Disproportionately high rates of childhood adversities, particularly among females, may partially explain despair in rural Appalachian areas. OUD treatment programs should conduct clinical assessments of trauma and integrate trauma-informed care into drug treatment, especially for female patients residing in rural Appalachia.
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Affiliation(s)
- Erin L Winstanley
- West Virginia University, School of Medicine and Rockefeller Neuroscience Institute, Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV, United States; West Virginia University, School of Medicine, Department of Neuroscience, United States.
| | - James J Mahoney
- West Virginia University, School of Medicine and Rockefeller Neuroscience Institute, Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV, United States; West Virginia University, School of Medicine, Department of Neuroscience, United States
| | - Laura R Lander
- West Virginia University, School of Medicine and Rockefeller Neuroscience Institute, Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV, United States; West Virginia University, School of Medicine, Department of Neuroscience, United States
| | - James H Berry
- West Virginia University, School of Medicine and Rockefeller Neuroscience Institute, Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV, United States; West Virginia University, School of Medicine, Department of Neuroscience, United States
| | - Patrick Marshalek
- West Virginia University, School of Medicine and Rockefeller Neuroscience Institute, Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV, United States; West Virginia University, School of Medicine, Department of Neuroscience, United States
| | - Wanhong Zheng
- West Virginia University, School of Medicine and Rockefeller Neuroscience Institute, Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV, United States; West Virginia University, School of Medicine, Department of Neuroscience, United States
| | - Marc W Haut
- West Virginia University, School of Medicine and Rockefeller Neuroscience Institute, Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV, United States; West Virginia University, School of Medicine, Department of Neuroscience, United States; West Virginia University, School of Medicine, Department of Neurology, United States; West Virginia University, School of Medicine, Department of Radiology, United States
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Milivojevic V, Angarita GA, Hermes G, Sinha R, Fox HC. Effects of Prazosin on Provoked Alcohol Craving and Autonomic and Neuroendocrine Response to Stress in Alcohol Use Disorder. Alcohol Clin Exp Res 2020; 44:1488-1496. [PMID: 32449942 DOI: 10.1111/acer.14378] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/13/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the hypothalamic-pituitary-adrenal axis responses, high stress-induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake. Thus, we hypothesized that prazosin would reduce stress-induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence. We secondarily also assessed the role of lifetime anxiety disorders on these prazosin effects. METHODS Forty inpatient treatment-seeking alcohol-dependent individuals were randomly assigned to receive placebo (n = 18) or 16 mg/d, T.I.D., prazosin (n = 22) in a double-blind manner, titrated over 2 weeks. In weeks 3 to 4 after achieving full dose, patients were exposed to 3 5-minute personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue), on 3 consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, heart rate, cortisol, and adrenocorticotropic hormone (ACTH) levels were assessed at baseline, following imagery and at repeated recovery timepoints. RESULTS Prazosin reduced stress cue-induced alcohol craving (p < 0.05) and stress- and alcohol cue-induced anxiety (p < 0.05) and increased heart rate responses in all imagery conditions (p < 0.05). Prazosin lowered basal cortisol and ACTH (p's < 0.05) and attenuated stress cue-induced rises in cortisol (p < 0.05) versus placebo. Finally, in those without lifetime anxiety disorder, the placebo group showed stress- and alcohol cue-induced increases in cortisol (p's < 0.05), while the prazosin group did not. CONCLUSIONS Prazosin may attenuate stress cue-induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders.
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Affiliation(s)
- Verica Milivojevic
- From the, Department of Psychiatry, (VM, GH, RS), The Yale Stress Center, Yale University School of Medicine, New Haven, Connecticut
| | - Gustavo A Angarita
- Clinical Neuroscience Research Unit, (GAA), Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut
| | - Gretchen Hermes
- From the, Department of Psychiatry, (VM, GH, RS), The Yale Stress Center, Yale University School of Medicine, New Haven, Connecticut
| | - Rajita Sinha
- From the, Department of Psychiatry, (VM, GH, RS), The Yale Stress Center, Yale University School of Medicine, New Haven, Connecticut
| | - Helen C Fox
- Department of Psychiatry, (HCF), Stony Brook University School of Medicine, Stony Brook, New York
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