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1
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Borland JM. A review of the effects of different types of social behaviors on the recruitment of neuropeptides and neurotransmitters in the nucleus accumbens. Front Neuroendocrinol 2025; 77:101175. [PMID: 39892577 DOI: 10.1016/j.yfrne.2025.101175] [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: 05/04/2024] [Revised: 01/25/2025] [Accepted: 01/26/2025] [Indexed: 02/04/2025]
Abstract
There is a lack of understanding of the neural mechanisms regulating the rewarding effects of social interactions. A significant contributor to this lack of clarity is the diversity of social behaviors and animal models utilized to investigate mechanisms. Other sources of the lack of clarity are the diversity of brain regions that can regulate social reward and the diversity of signaling pathways that regulate reward. To provide some clarity into the mechanisms of social reward, this review focused on the brain region most implicated in reward for multiple stimuli, the nucleus accumbens, and surveyed (systematically reviewed) studies that investigated the relationship between social interaction and five signaling systems implicated in the regulation of reward and social behavior: oxytocin, vasopressin, serotonin, opioids and endocannabinoids. Moreover, all of these studies were organized by the type of social behavior studied: affiliative interactions, play behavior, aggression, social defeat, sex behavior, pair-bonding, parental behavior and social isolation. From this survey and organization, this review concludes that oxytocin, endocannabinoids and mu-opioid receptors in the nucleus accumbens positively regulate the rewarding social behaviors, and kappa-opioid receptors negatively regulate the rewarding social behaviors. The opposite profile is observed for these signaling systems for the aversive social behaviors. More studies are needed to investigate the directional role of the serotonin system in the nucleus accumbens in the regulation of many types of social behaviors, and vasopressin likely does not act in the nucleus accumbens in the regulation of the valence of social behaviors. Many of these different signaling systems are also interdependent of one another in the regulation of different types of social behaviors. Finally, the interaction of these signaling systems with dopamine in the nucleus accumbens is briefly discussed.
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Yang HR, Li ZY, Zhu H, Wu H, Xie C, Wang XQ, Huang CS, Geng WJ. Mapping the current trends and hotspots of transcranial magnetic stimulation-based addiction treatment from 2001-2023: A bibliometric analysis. World J Meta-Anal 2025; 13:104644. [DOI: 10.13105/wjma.v13.i1.104644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/26/2025] [Accepted: 02/12/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND The prevalence of addiction makes it a significant public health issue. Recently, transcranial magnetic stimulation (TMS) has garnered significant attention as a promising treatment for addiction.
AIM To analyze development trends and research hotspots in TMS-based addiction treatment using a bibliometric approach.
METHODS Articles on TMS-based addiction treatment from 2001 to 2023 were sourced from the Science Citation Index Expanded in the Web of Science Core Collection. CiteSpace software, VOSviewer, the "bibliometrix" R software package, and the bibliometric online analysis platform were used to analyze the current publication trends and hotspots.
RESULTS Total 190 articles on TMS-based addiction treatment were identified, with clinical studies being the most prevalent. The United States led in both publication volume and international collaborations. Medical University of South Carolina and Zangen A were the most productive institution and author, respectively. Neurobiology, alcohol use disorder, and repetitive TMS were the most recent research hotspots.
CONCLUSION Future research should focus on the neurobiological mechanisms underlying TMS-based addiction treatment. This study offers comprehensive insights and recommendations for advancing research on TMS-based addiction treatment.
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Affiliation(s)
- Hao-Ran Yang
- School of Educational Sciences, Chongqing Normal University, Chongqing 400030, China
| | - Zheng-Yu Li
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Hao Zhu
- Department of Anesthesiology, The First Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang Province, China
| | - Hong Wu
- Department of Anesthesiology, The First Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang Province, China
| | - Chen Xie
- Department of Anesthesiology, The First People's Hospital of Huzhou, Huzhou 313000, Zhejiang Province, China
| | - Xin-Qiang Wang
- Department of Anesthesiology, The First People's Hospital of Huzhou, Huzhou 313000, Zhejiang Province, China
| | - Chang-Shun Huang
- Department of Anesthesiology, The First Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang Province, China
| | - Wu-Jun Geng
- Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
- Department of Pain, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Gyetvai BM, Vadasz C. Pleiotropic Effects of Grm7/ GRM7 in Shaping Neurodevelopmental Pathways and the Neural Substrate of Complex Behaviors and Disorders. Biomolecules 2025; 15:392. [PMID: 40149928 PMCID: PMC11940234 DOI: 10.3390/biom15030392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/08/2025] [Accepted: 02/10/2025] [Indexed: 03/29/2025] Open
Abstract
Natural gene variants of metabotropic glutamate receptor subtype 7 (Grm7), coding for mGluR7, affect individuals' alcohol-drinking preference. Psychopharmacological investigations have suggested that mGluR7 is also involved in responses to cocaine, morphine, and nicotine exposures. We review the pleiotropic effects of Grm7 and the principle of recombinant quantitative trait locus introgression (RQI), which led to the discovery of the first mammalian quantitative gene accounting for alcohol-drinking preference. Grm7/GRM7 can play important roles in mammalian ontogenesis, brain development, and predisposition to addiction. It is also involved in other behavioral phenotypes, including emotion, stress, motivated cognition, defensive behavior, and pain-related symptoms. This review identified pleiotropy and the modulation of neurobehavioral processes by variations in the gene Grm7/GRM7. Patterns of pleiotropic genes can form oligogenic architectures whosecombined additive and interaction effects can significantly predispose individuals to the expressions of disorders. Identifying and characterizing pleiotropic genes are necessary for understanding the expressions of complex traits. This requires tasks, such as discovering and identifying novel genetic elements of the genetic architecture, which are unsuitable for AI but require classical experimental genetics.
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Affiliation(s)
- Beatrix M. Gyetvai
- Laboratory of Neurobehavior Genetics, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY 10962, USA;
| | - Csaba Vadasz
- Laboratory of Neurobehavior Genetics, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY 10962, USA;
- Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA
- Kalymma, Stony Point, New York, NY 10980, USA
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Júnior REM, Pedersen ASB, Ferreira RM, de Asevedo GH, Mendes GL, Ribeiro K, Maioli TU, de Faria AMC, Brunialti-Godard AL. Behavioral changes and transcriptional regulation of mesolimbic dopaminergic genes in a mouse model of binge eating disorder by diet intermittent access. J Nutr Biochem 2025; 135:109784. [PMID: 39426552 DOI: 10.1016/j.jnutbio.2024.109784] [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: 12/06/2023] [Revised: 08/02/2024] [Accepted: 10/12/2024] [Indexed: 10/21/2024]
Abstract
Binge Eating Disorder (BED) is among the most prevalent eating disorders worldwide. It is characterized by recurrent episodes of excessive consumption of palatable foods in short periods, accompanied by a sense of loss of control and distress around the episode, which tends to worsen over time. The mesolimbic dopaminergic system influences on reinforcement and reward-seeking behaviors is implicated in the disorder's pathogenesis. Animal models that replicate the clinical conditions observed in humans, including the disorder progression, are essential for understanding the underlying physiological mechanisms of BED. This study aimed to evaluate binge eating behavior induced by intermittent High Sugar and Butter (HSB) diet access in mice, their phenotypes, transcriptional regulation of mesolimbic dopaminergic system genes, and behavior. Thus, mice were subdivided into three groups: CHOW (maintenance diet only), HSB-i (maintenance diet with thrice-weekly access to HSB), and HSB (continuous access to HSB). Animals were subjected to marble-burying and light-dark box behavioral tests, and transcriptional regulation was evaluated by RT-qPCR. The results indicated that the HSB-i group established a feeding pattern of significantly more kilocalories on days when HSB was available and reduced intake on non-HSB days similar to human binge eating. Over time, binge episodes intensified, potentially indicating a tolerance effect. Additionally, these animals behave differently towards preferring the HSB diet and exhibited altered transcriptional regulation of the Drd1, Slc6a3, and Lrrk2 genes. Our study provides a mouse model that reflects human BED, showing a progression in binge episodes and mesolimbic dopamine pathway involvement, suggesting targets for future therapeutic interventions.
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Affiliation(s)
- Renato Elias Moreira Júnior
- Laboratório de Genética Animal e Humana, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
| | - Agatha Sondertoft Braga Pedersen
- Laboratório de Genética Animal e Humana, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Raquel Mary Ferreira
- Laboratório de Genética Animal e Humana, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Guilherme Henrique de Asevedo
- Laboratório de Genética Animal e Humana, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Grazielle Laudares Mendes
- Laboratório de Genética Animal e Humana, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Karine Ribeiro
- Laboratório de Genética Animal e Humana, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Tatiani Uceli Maioli
- Laboratório de Imunobiologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ana Maria Caetano de Faria
- Laboratório de Imunobiologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ana Lúcia Brunialti-Godard
- Laboratório de Genética Animal e Humana, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Richard JM, Newell B, Muruganandan P, Janak PH, Saunders BT. Pavlovian cue-evoked alcohol seeking is disrupted by ventral pallidal inhibition. ADDICTION NEUROSCIENCE 2024; 13:100186. [PMID: 39640360 PMCID: PMC11619284 DOI: 10.1016/j.addicn.2024.100186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Cues paired with alcohol can be potent drivers of craving, alcohol-seeking, consumption, and relapse. While the ventral pallidum is implicated in appetitive and consummatory responses across several reward classes and types of behaviors, its role in behavioral responses to Pavlovian alcohol cues has not previously been established. Here, we tested the impact of optogenetic inhibition of ventral pallidum on Pavlovian-conditioned alcohol-seeking in male Long Evans rats. Rats underwent Pavlovian conditioning with an auditory cue predicting alcohol delivery to a reward port and a control cue predicting no alcohol delivery, until they consistently entered the reward port more during the alcohol cue than the control cue. We then tested the within-session effects of optogenetic inhibition during 50% of cue presentations. We found that optogenetic inhibition of ventral pallidum during the alcohol cue reduced port entry likelihood and time spent in the port, and increased port entry latency. Overall, these results suggest that normal ventral pallidum activity is necessary for Pavlovian alcohol-seeking.
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Affiliation(s)
- Jocelyn M. Richard
- Department of Neuroscience, University of Minnesota, Minneapolis, MN 55415
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN 55415
| | - Bailey Newell
- Department of Neuroscience, University of Minnesota, Minneapolis, MN 55415
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN 55415
| | - Preethi Muruganandan
- Department of Neuroscience, University of Minnesota, Minneapolis, MN 55415
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN 55415
| | - Patricia H. Janak
- Department of Psychological and Brain Sciences, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218
- The Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21218
| | - Benjamin T. Saunders
- Department of Neuroscience, University of Minnesota, Minneapolis, MN 55415
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN 55415
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Luján MÁ, Young-Morrison R, Aroni S, Katona I, Melis M, Cheer JF. Dynamic overrepresentation of accumbal cues in food- and opioid-seeking rats after prenatal THC exposure. SCIENCE ADVANCES 2024; 10:eadq5652. [PMID: 39514650 PMCID: PMC11546747 DOI: 10.1126/sciadv.adq5652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 10/07/2024] [Indexed: 11/16/2024]
Abstract
The increasing prevalence of cannabis use during pregnancy has raised medical concerns, primarily related to Δ9-tetrahydrocannabinol (THC), which readily crosses the placenta and affects fetal brain development. Previous research has identified dopaminergic alterations related to maternal THC consumption. However, the consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during reward pursuit have not been determined. Here, we characterize PCE rats during food or opioid-maintained reward seeking. We find that the supramotivational phenotype of PCE rats is independent of value-based processing and is instead related to augmented reinforcing efficiency of opioid rewards. Our findings reveal that prenatal THC exposure leads to increased cue-evoked dopamine responses and an overrepresentation of effort-driven striatal encoding patterns. Recapitulating clinical findings, drug-related PCE adaptations were more pronounced in males, who showed increased vulnerability for relapse. Collectively, these findings indicate that prenatal THC exposure in male rats engenders a pronounced neurodevelopmental susceptibility to addiction-like disorders.
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Affiliation(s)
- Miguel Á. Luján
- Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Reana Young-Morrison
- Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Sonia Aroni
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy
| | - István Katona
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - Miriam Melis
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy
| | - Joseph F. Cheer
- Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
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Martinelli S, Mazzotta A, Longaroni M, Petrucciani N. Potential role of glucagon-like peptide-1 (GLP-1) receptor agonists in substance use disorder: A systematic review of randomized trials. Drug Alcohol Depend 2024; 264:112424. [PMID: 39288591 DOI: 10.1016/j.drugalcdep.2024.112424] [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] [Received: 05/10/2024] [Revised: 08/17/2024] [Accepted: 08/18/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Increasing evidence suggests that GLP-1 receptor agonists (GLP-1RA) have a potential use in addiction treatment. Few studies have assessed the impact of GLP-1RA on substance use disorder (SUD), particularly in humans. The study aimed to do systematic review of clinical trials to assess GLP-1RA's effect on reducing SUD in patients. METHODS The scientific literature was reviewed using the MEDLINE, Scopus and Cochrane Library databases, following PRISMA guidelines. Studies including patients with a diagnosis of SU who were treated with GLP-1RA were selected. The primary outcome was GLP-1RA's therapeutic effect on SUD, and the secondary outcomes were therapeutic effects of GLP-1RA on weight, BMI and HbA1c. RESULTS 1218 studies were retrieved, resulting in 507 papers after title and abstract screening. Following full-text review, only 5 articles met inclusion criteria. We incorporated a total of 630 participants utilizing Exenatide (n=3) and Dulaglutide (n=2) as GLP-1RAs. Therapeutic effect of GLP-1RA on SUD was assessed in 5 studies, with 3 demonstrating a significant decrease in SUD (alcohol and nicotine). GLP-1RA's impact on body weight, BMI, and HbA1c, was reported in 3 studies. These revealed a notable reduction in these parameters among the GLP-1RA treated group. CONCLUSION This review will give an overview of current new findings in human studies; we suggest that the effects of GLP-1RA in SUD is a possible new option of therapy in addiction medicine.
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Affiliation(s)
- Silvia Martinelli
- Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy; Department of Mental Health, Local Health Authority Viterbo, Viterbo, Italy
| | - Alessandro Mazzotta
- Department of Surgery, M.G. General Vannini Hospital, Istituto Figlie Di San Camillo, Rome, Italy
| | - Mattia Longaroni
- Department of Surgery, Santa Maria della Misericordia Hospital, University of Perugia, Italy
| | - Niccolò Petrucciani
- Department of Medical and Surgical Sciences and Translational Medicine, Division of General and Hepatobiliary Surgery, St. Andrea Hospital, Sapienza University of Rome, Italy.
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Fesenko Z, Ptukha M, da Silva MM, de Carvalho RSM, Tsytsarev V, Gainetdinov RR, Faber J, Volnova AB. Electrophysiological and Behavioral Markers of Hyperdopaminergia in DAT-KO Rats. Biomedicines 2024; 12:2114. [PMID: 39335627 PMCID: PMC11428849 DOI: 10.3390/biomedicines12092114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 09/10/2024] [Accepted: 09/14/2024] [Indexed: 09/30/2024] Open
Abstract
Background/Objectives: Dopamine dysfunction (DA) is a hallmark of many neurological disorders. In this case, the mechanism of changes in dopamine transmission on behavior remains unclear. This study is a look into the intricate link between disrupted DA signaling, neuronal activity patterns, and behavioral abnormalities in a hyperdopaminergic animal model. Methods: To study the relationship between altered DA levels, neuronal activity, and behavioral deficits, local field potentials (LFPs) were recorded during four different behaviors in dopamine transporter knockout rats (DAT-KO). At the same time, local field potentials were recorded in the striatum and prefrontal cortex. Correlates of LFP and accompanying behavioral patterns in genetically modified (DAT-KO) and control animals were studied. Results: DAT-KO rats exhibited desynchronization between LFPs of the striatum and prefrontal cortex, particularly during exploratory behavior. A suppressive effect of high dopamine levels on the striatum was also observed. Wild-type rats showed greater variability in LFP patterns across certain behaviors, while DAT-KO rats showed more uniform patterns. Conclusions: The decisive role of the synchrony of STR and PFC neurons in the organization of motor acts has been revealed. The greater variability of control animals in certain forms of behavior probably suggests greater adaptability. More uniform patterns in DAT-KO rats, indicating a loss of striatal flexibility when adapting to specific motor tasks. It is likely that hyperdopaminergy in the DAT-KO rat reduces the efficiency of information processing due to less synchronized activity during active behavior.
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Affiliation(s)
- Zoia Fesenko
- Institute of Translational Biomedicine, Saint Petersburg State University, Saint Petersburg 199034, Russia
| | - Maria Ptukha
- Centre for Youth Mental Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria 3010, Australia;
| | - Marcelo M. da Silva
- Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil
| | - Raquel S. Marques de Carvalho
- Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil
| | - Vassiliy Tsytsarev
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Raul R. Gainetdinov
- Institute of Translational Biomedicine, Saint Petersburg State University, Saint Petersburg 199034, Russia
- Saint Petersburg University Hospital, Saint Petersburg 190121, Russia
| | - Jean Faber
- Department of Neurology and Neurosurgery, Division of Neuroscience, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil
| | - Anna B. Volnova
- Institute of Translational Biomedicine, Saint Petersburg State University, Saint Petersburg 199034, Russia
- Biological Faculty, Saint Petersburg State University, Saint Petersburg 199034, Russia
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Kim OH, Jeon KO, Kim G, Jang CG, Yoon SS, Jang EY. The neuropharmacological properties of α-pyrrolidinobutiothiophenone, a new synthetic cathinone, in rodents; role of the dopaminergic system. Br J Pharmacol 2024; 181:3462-3482. [PMID: 38772548 DOI: 10.1111/bph.16422] [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: 07/10/2023] [Revised: 04/14/2024] [Accepted: 04/19/2024] [Indexed: 05/23/2024] Open
Abstract
BACKGROUND AND PURPOSE α-Pyrrolidinobutiothiophenone (α-PBT) is a chemical derivative of cathinone, a structural analogue of amphetamine. Until now, there have been a few previous neurochemical or neurobehavioural studies on the abuse potential of α-PBT. EXPERIMENTAL APPROACH We examined the abuse potential of α-PBT by measuring psychomotor, rewarding, and reinforcing properties and methamphetamine-like discriminative stimulus effects in rodents using locomotor activity, conditioned place preference, self-administration, and drug discrimination studies. To clarify the underlying neuropharmacological mechanisms, we measured dopamine levels and neuronal activation in the dorsal striatum. In addition, we investigated the role of the dopamine D1 receptor or D2 receptors in α-PBT-induced hyperlocomotor activity, conditioned place preference, and the methamphetamine-like discriminative stimulus effect of α-PBT in rodents. KEY RESULTS α-PBT promoted hyperlocomotor activity in mice. α-PBT induced drug-paired place preference in mice and supported self-administration in rats. In a drug discrimination experiment, α-PBT fully substituted for the discriminative stimulus effects of methamphetamine in rats. Furthermore, α-PBT increased dopamine levels and c-Fos expression in the dorsal striatum of mice, which was associated with these behaviours. Finally, pretreatment with the D1 receptor antagonist SCH23390 or the D2 receptors antagonist eticlopride significantly attenuated acute or repeated α-PBT-induced hyperlocomotor activity, place preference, and the methamphetamine-like discriminative stimulus effects in rodents. CONCLUSIONS AND IMPLICATIONS These findings suggest that α-PBT has abuse potential at the highest dose tested via enhanced dopaminergic transmission in the dorsal striatum of rodents. The results provide scientific evidence for the legal restrictions of the recreational use of α-PBT.
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Affiliation(s)
- Oc-Hee Kim
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Kyung Oh Jeon
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, Daejeon, Republic of Korea
- Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, Republic of Korea
| | - Gihyeon Kim
- Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu, Republic of Korea
| | - Choon-Gon Jang
- Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Seong Shoon Yoon
- Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu, Republic of Korea
| | - Eun Young Jang
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, Daejeon, Republic of Korea
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10
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Foyzun T, Whiting M, Velasco KK, Jacobsen JC, Connor M, Grimsey NL. Single nucleotide polymorphisms in the cannabinoid CB 2 receptor: Molecular pharmacology and disease associations. Br J Pharmacol 2024; 181:2391-2412. [PMID: 38802979 DOI: 10.1111/bph.16383] [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: 11/30/2023] [Revised: 02/26/2024] [Accepted: 03/09/2024] [Indexed: 05/29/2024] Open
Abstract
Preclinical evidence implicating cannabinoid receptor 2 (CB2) in various diseases has led researchers to question whether CB2 genetics influence aetiology or progression. Associations between conditions and genetic loci are often studied via single nucleotide polymorphism (SNP) prevalence in case versus control populations. In the CNR2 coding exon, ~36 SNPs have high overall population prevalence (minor allele frequencies [MAF] ~37%), including non-synonymous SNP (ns-SNP) rs2501432 encoding CB2 63Q/R. Interspersed are ~27 lower frequency SNPs, four being ns-SNPs. CNR2 introns also harbour numerous SNPs. This review summarises CB2 ns-SNP molecular pharmacology and evaluates evidence from ~70 studies investigating CB2 genetic variants with proposed linkage to disease. Although CNR2 genetic variation has been associated with a wide variety of conditions, including osteoporosis, immune-related disorders, and mental illnesses, further work is required to robustly validate CNR2 disease links and clarify specific mechanisms linking CNR2 genetic variation to disease pathophysiology and potential drug responses.
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Affiliation(s)
- Tahira Foyzun
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, New South Wales, Australia
| | - Maddie Whiting
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Kate K Velasco
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Jessie C Jacobsen
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
- Centre for Brain Research, University of Auckland, Auckland, New Zealand
| | - Mark Connor
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, New South Wales, Australia
| | - Natasha L Grimsey
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Centre for Brain Research, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
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11
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Arillotta D, Floresta G, Papanti Pelletier GD, Guirguis A, Corkery JM, Martinotti G, Schifano F. Exploring the Potential Impact of GLP-1 Receptor Agonists on Substance Use, Compulsive Behavior, and Libido: Insights from Social Media Using a Mixed-Methods Approach. Brain Sci 2024; 14:617. [PMID: 38928616 PMCID: PMC11202225 DOI: 10.3390/brainsci14060617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is involved in a range of central and peripheral pathways related to appetitive behavior. Hence, this study explored the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on substance and behavioral addictions, including alcohol, caffeine, nicotine, cannabis, psychostimulants, compulsive shopping, and sex drive/libido. Data were collected from various social platforms. Keywords related to GLP-1 RAs and substance/behavioral addiction were used to extract relevant comments. The study employed a mixed-methods approach to analyze online discussions posted from December 2019 to June 2023 and collected using a specialized web application. Reddit entries were the focus here due to limited data from other platforms, such as TikTok and YouTube. A total of 5859 threads and related comments were extracted from six subreddits, which included threads about GLP-1 RAs drugs and associated brand names. To obtain relevant posts, keywords related to potential substance use and compulsive behavior were selected. Further analysis involved two main steps: (1) manually coding posts based on users' references to the potential impact of GLP-1 RAs on substance use and non-substance habits, excluding irrelevant or unclear comments; (2) performing a thematic analysis on the dataset of keywords, using AI-assisted techniques followed by the manual revision of the generated themes. Second, a thematic analysis was performed on the keyword-related dataset, using AI-assisted techniques followed by the manual revision of the generated themes. In total, 29.75% of alcohol-related; 22.22% of caffeine-related; and 23.08% of nicotine-related comments clearly stated a cessation of the intake of these substances following the start of GLP-1 RAs prescription. Conversely, mixed results were found for cannabis intake, and only limited, anecdotal data were made available for cocaine, entactogens, and dissociative drugs' misuse. Regarding behavioral addictions, 21.35% of comments reported a compulsive shopping interruption, whilst the sexual drive/libido elements reportedly increased in several users. The current mixed-methods approach appeared to be a useful tool in gaining insight into complex topics such as the effects of GLP-1 RAs on substance and non-substance addiction-related disorders; some GLP-1 RA-related mental health benefits could also be inferred from here. Overall, it appeared that GLP-1 RAs may show the potential to target both substance craving and maladaptive/addictive behaviors, although further empirical research is needed.
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Affiliation(s)
- Davide Arillotta
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, 50121 Florence, Italy
| | - Giuseppe Floresta
- Department of Drug and Health Sciences, University of Catania, 95124 Catania, Italy;
| | - G. Duccio Papanti Pelletier
- Tolmezzo Community Mental Health Centre, ASUFC Mental Health Department, Via Giuliano Bonanni, 2, 33028 Tolmezzo, Italy;
| | - Amira Guirguis
- Pharmacy, Faculty of Medicine, Health and Life Science, Swansea University, Singleton Campus, Swansea SA2 8PP, Wales, UK;
| | - John Martin Corkery
- Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, UK; (J.M.C.); (F.S.)
| | - Giovanni Martinotti
- Department of Neurosciences, Imaging and Clinical Sciences, University of Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), Institute of Advanced Biomedical Technology (ITAB), University of Chieti-Pescara, Via dei Vestini 21, 66100 Chieti, Italy
| | - Fabrizio Schifano
- Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, UK; (J.M.C.); (F.S.)
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12
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Alsalloum I, Moskaliuk VS, Rakhov IA, Bazovkina DV, Kulikov AV. The C886T Mutation in the Th Gene Reduces the Activity of Tyrosine Hydroxylase in the Mouse Brain. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:1024-1030. [PMID: 38981698 DOI: 10.1134/s000629792406004x] [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: 03/16/2024] [Revised: 04/15/2024] [Accepted: 04/25/2024] [Indexed: 07/11/2024]
Abstract
Tyrosine hydroxylase (TH) catalyzes hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine, the initial and rate-limiting step in the synthesis of dopamine, noradrenaline, and adrenaline. Mutations in the human TH gene are associated with hereditary motor disorders. The common C886T mutation identified in the mouse Th gene results in the R278H substitution in the enzyme molecule. We investigated the impact of this mutation on the TH activity in the mouse midbrain. The TH activity in the midbrain of Mus musculus castaneus (CAST) mice homozygous for the 886C allele was higher compared to C57BL/6 and DBA/2 mice homozygous for the 886T allele. Notably, this difference in the enzyme activity was not associated with changes in the Th gene mRNA levels and TH protein content. Analysis of the TH activity in the midbrain in mice from the F2 population obtained by crossbreeding of C57BL/6 and CAST mice revealed that the 886C allele is associated with a high TH activity. Moreover, this allele showed complete dominance over the 886T allele. However, the C886T mutation did not affect the levels of TH protein in the midbrain. These findings demonstrate that the C886T mutation is a major genetic factor determining the activity of TH in the midbrain of common laboratory mouse strains. Moreover, it represents the first common spontaneous mutation in the mouse Th gene whose influence on the enzyme activity has been demonstrated. These results will help to understand the role of TH in the development of adaptive and pathological behavior, elucidate molecular mechanisms regulating the activity of TH, and explore pharmacological agents for modulating its function.
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Affiliation(s)
- Ismail Alsalloum
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, 630090, Russia
- Novosibirsk State University, Novosibirsk, 630090, Russia
| | - Vitalii S Moskaliuk
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Ilya A Rakhov
- Novosibirsk State University, Novosibirsk, 630090, Russia
| | - Daria V Bazovkina
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Alexander V Kulikov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, 630090, Russia.
- Novosibirsk State University, Novosibirsk, 630090, Russia
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13
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Luján MÁ, Young-Morrison R, Aroni S, Katona I, Melis M, Cheer J. Dynamic Overrepresentation of Accumbal Cues in Food- and Opioid-Seeking Rats after Prenatal THC Exposure. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.06.592839. [PMID: 38766015 PMCID: PMC11100737 DOI: 10.1101/2024.05.06.592839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
The increasing prevalence of cannabis use during pregnancy has raised significant medical concerns, primarily related to the presence of Δ9-tetrahydrocannabinol (THC), which readily crosses the placenta and impacts fetal brain development. Previous research has identified midbrain dopaminergic neuronal alterations related to maternal THC consumption. However, the enduring consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during voluntary reward pursuit have not been specifically determined. Here, we characterize PCE rats during food (palatable pellets) or opioid (remifentanyl)-maintained reward seeking. We find that the supra motivational phenotype of PCE rats is independent of value-based processing and is instead related to augmented reinforcing efficiency of opioid rewards. Our findings reveal that in utero THC exposure leads to increased cue-evoked dopamine release responses and an overrepresentation of cue-aligned, effort-driven striatal patterns of encoding. Recapitulating findings in humans, drug-related neurobiological adaptations of PCE were more pronounced in males, who similarly showed increased vulnerability for relapse. Collectively, these findings indicate that prenatal THC exposure in male rats engenders a pronounced neurodevelopmental susceptibility to addiction-like disorders later in life.
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14
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Farmer G, Lloyd J. Two Sides of the Same Virtual Coin: Investigating Psychosocial Effects of Video Game Play, including Stress Relief Motivations as a Gateway to Problematic Video Game Usage. Healthcare (Basel) 2024; 12:772. [PMID: 38610194 PMCID: PMC11011277 DOI: 10.3390/healthcare12070772] [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: 01/23/2024] [Revised: 03/26/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Video gamers can play to negate the psychological impact of stress, which may become problematic when users over-rely on the stress relief potential of gaming. This study used a repeated measures experimental design to investigate the relationships between stress, video gaming, and problematic video gaming behaviours in a convenience sample of 40 students at a UK university. The results indicated that positive affect increased and negative affect decreased, whilst a biological stress measure (instantaneous pulse rate) also decreased after a short video gaming session (t(36) = 4.82, p < 0.001, d = 0.79). The results also suggested that video gaming can act as a short-term buffer against the physiological impact of stress. Further research should focus on testing individuals who have been tested for gaming disorder, as opposed to the general population. Research could also utilise variations of the methodological framework used in this study to examine the intensity of a stress relief effect under different social situations. The study's findings in relation to published works are also discussed.
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Affiliation(s)
- George Farmer
- Westminster Centre for Psychological Sciences, University of Westminster, London W1W 6UW, UK
| | - Joanne Lloyd
- Cyberpsychology Research—University of Wolverhampton, School of Psychology, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton WV1 1LY, UK;
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15
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McGraw JJ, Goldsmith RS, Cromwell HC. Altered reward sensitivity to sucrose outcomes prior to drug exposure in alcohol preferring rats. Pharmacol Biochem Behav 2024; 237:173724. [PMID: 38340990 DOI: 10.1016/j.pbb.2024.173724] [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: 03/16/2023] [Revised: 01/19/2024] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
Addiction involves key impairments in reward sensitivity (RS). The current study explored impaired RS to natural reward as a predisposing factor to addictive-like behavior. Alcohol preferring (P) rats are selectively bred based on significantly greater ethanol consumption and preference and offer the ability to inspect differences in subjects with a positive family history of addictive-like behavior. P rat's RS was compared to RS in the well-used Sprague-Dawley (SD) strain. To assess RS in a novel manner, instrumental incentive contrast, discrimination and consumption of sucrose solution were examined. Animals performed in a free operant situation for different sucrose concentration solutions using a block of 'mixed' trials with alternating outcome concentrations (e.g., 5 and 10 % sucrose) to change outcome value in a predictable manner. Animals also performed for reward in blocks of single outcome trials (5 or 10 or 20 or 40 % sucrose daily exposure) surrounding the mixed block. RS (e.g., reward discrimination and contrast effects between and within-sessions) was measured by changes in trials completed, instrumental response latency and consumption. P rats expressed an altered profile of RS with a greater tendency toward equivalent responding to different outcomes within the same session and an absence of incentive contrast from diverse reward comparisons. In contrast, SD animals expressed within-session reward discrimination and a subset of incentive contrast effects. These effects were moderated by food deprivation more consistently in SD compared to P rats. P rat alterations in processing natural rewards could predispose them to addictive-like behaviors including greater alcohol consumption and preference.
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Affiliation(s)
- Justin J McGraw
- Department of Psychology and John Paul Scott Center for Neuroscience, Mind and Behavior, Bowling Green State University, Bowling Green, OH 43403, United States of America
| | - Robert S Goldsmith
- Department of Psychology and John Paul Scott Center for Neuroscience, Mind and Behavior, Bowling Green State University, Bowling Green, OH 43403, United States of America
| | - Howard C Cromwell
- Department of Psychology and John Paul Scott Center for Neuroscience, Mind and Behavior, Bowling Green State University, Bowling Green, OH 43403, United States of America.
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16
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Richard JM, Armstrong A, Newell B, Muruganandan P, Janak PH, Saunders BT. Pavlovian cue-evoked alcohol seeking is disrupted by ventral pallidal inhibition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.14.585064. [PMID: 38559136 PMCID: PMC10980019 DOI: 10.1101/2024.03.14.585064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Cues paired with alcohol can be potent drivers of craving, alcohol-seeking, consumption, and relapse. While the ventral pallidum is implicated in appetitive and consummatory responses across several reward classes and types of behaviors, its role in behavioral responses to Pavlovian alcohol cues has not previously been established. Here, we tested the impact of optogenetic inhibition of ventral pallidum on Pavlovian-conditioned alcohol-seeking in male Long Evans rats. Rats underwent Pavlovian conditioning with an auditory cue predicting alcohol delivery to a reward port and a control cue predicting no alcohol delivery, until they consistently entered the reward port more during the alcohol cue than the control cue. We then tested the within-session effects of optogenetic inhibition during 50% of cue presentations. We found that optogenetic inhibition of ventral pallidum during the alcohol cue reduced port entry likelihood and time spent in the port, and increased port entry latency. Overall, these results suggest that normal ventral pallidum activity is necessary for Pavlovian alcohol-seeking.
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Affiliation(s)
- Jocelyn M. Richard
- Department of Neuroscience, University of Minnesota, Minneapolis, MN
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN
| | - Anne Armstrong
- Department of Psychological and Brain Sciences, Krieger School of Arts and Sciences Johns Hopkins University, Baltimore, MD
| | - Bailey Newell
- Department of Neuroscience, University of Minnesota, Minneapolis, MN
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN
| | - Preethi Muruganandan
- Department of Neuroscience, University of Minnesota, Minneapolis, MN
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN
| | - Patricia H. Janak
- Department of Psychological and Brain Sciences, Krieger School of Arts and Sciences Johns Hopkins University, Baltimore, MD
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD
| | - Benjamin T. Saunders
- Department of Neuroscience, University of Minnesota, Minneapolis, MN
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN
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17
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Ouaidat S, Amaral IM, Monteiro DG, Harati H, Hofer A, El Rawas R. Orexins/Hypocretins: Gatekeepers of Social Interaction and Motivation. Int J Mol Sci 2024; 25:2609. [PMID: 38473854 PMCID: PMC10931973 DOI: 10.3390/ijms25052609] [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: 01/16/2024] [Revised: 02/12/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Ever since the discovery of the brain's orexin/hypocretin system, most research was directed toward unveiling its contribution to the normal functioning of individuals. The investigation of reward-seeking behaviors then gained a lot of attention once the distribution of orexinergic neurons was revealed. Here, we discuss findings on the involvement of orexins in social interaction, a natural reward type. While some studies have succeeded in defining the relationship between orexin and social interaction, the controversy regarding its nature (direct or inverse relation) raises questions about what aspects have been overlooked until now. Upon examining the literature, we identified a research gap concerning conditions influencing the impact of orexins on social behavior expression. In this review, we introduce a number of factors (e.g., stress, orexin's source) that must be considered while studying the role of orexins in social interaction. Furthermore, we refer to published research to investigate the stage at which orexins affect social interaction and we highlight the nucleus accumbens (NAc) shell's role in social interaction and other rewarding behaviors. Finally, the underlying orexin molecular pathway influencing social motivation in particular illnesses is proposed. We conclude that orexin's impact on social interaction is multifactorial and depends on specific conditions available at a time.
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Affiliation(s)
- Sara Ouaidat
- Division of Psychiatry I, Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, Medical University Innsbruck, 6020 Innsbruck, Austria
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut P.O. Box 1533, Lebanon
| | - Inês M. Amaral
- Division of Psychiatry I, Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Diogo G. Monteiro
- Division of Psychiatry I, Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Hayat Harati
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut P.O. Box 1533, Lebanon
| | - Alex Hofer
- Division of Psychiatry I, Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Rana El Rawas
- Division of Psychiatry I, Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, Medical University Innsbruck, 6020 Innsbruck, Austria
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18
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Wolff AR, Saunders BT. Sensory Cues Potentiate VTA Dopamine Mediated Reinforcement. eNeuro 2024; 11:ENEURO.0421-23.2024. [PMID: 38238080 PMCID: PMC10875637 DOI: 10.1523/eneuro.0421-23.2024] [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: 10/16/2023] [Revised: 12/19/2023] [Accepted: 01/04/2024] [Indexed: 01/25/2024] Open
Abstract
Sensory cues are critical for shaping decisions and invigorating actions during reward seeking. Dopamine neurons in the ventral tegmental area (VTA) are central in this process, supporting associative learning in Pavlovian and instrumental settings. Studies of intracranial self-stimulation (ICSS) behavior, which show that animals will work hard to receive stimulation of dopamine neurons, support the notion that dopamine transmits a reward or value signal to support learning. Recent studies have begun to question this, however, emphasizing dopamine's value-free functions, leaving its contribution to behavioral reinforcement somewhat muddled. Here, we investigated the role of sensory stimuli in dopamine-mediated reinforcement, using an optogenetic ICSS paradigm in tyrosine hydroxylase (TH)-Cre rats. We find that while VTA dopamine neuron activation in the absence of explicit external cues is sufficient to maintain robust self-stimulation, the presence of cues dramatically potentiates ICSS behavior. Our results support a framework where dopamine can have some base value as a reinforcer, but the impact of this signal is modulated heavily by the sensory learning context.
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Affiliation(s)
- Amy R Wolff
- Department of Neuroscience, University of Minnesota, Minneapolis 55455, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis 55455, Minnesota
| | - Benjamin T Saunders
- Department of Neuroscience, University of Minnesota, Minneapolis 55455, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis 55455, Minnesota
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19
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Yang Y, Wei X, Tian J, Zhu Y, Jia S, Shu Q. Scalp electroacupuncture targeting the VTA DA neurons to relieve negative emotions and promote the alleviation of chronic pain. Front Neurosci 2023; 17:1323727. [PMID: 38188034 PMCID: PMC10771389 DOI: 10.3389/fnins.2023.1323727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 11/30/2023] [Indexed: 01/09/2024] Open
Abstract
Object Chronic pain and negative emotions are often linked, and both can impact the reward circuit. The use of electroacupuncture (EA) has been found to regulate and improve these conditions. This study explores the potential mechanism of chronic pain relief by adding acupoints with emotional regulation effect to the basis of routine EA analgesia, to optimize the acupoint compatibility scheme of EA in the treatment of analgesia. Method For this study, 42 male Wistar rats were used. Recombinant adeno-associated viruses were used to label and regulate the activity of dopamine (DA) neurons. The rat model was established by complete Freund's adjuvant (CFA). Lower limb electroacupuncture (LEA) was applied to the ST36 and BL60 acupoints. In addition, LEA + scalp EA (SEA) was given using the GV20 and GV24+ acupoints besides ST36 and BL60. To evaluate the pain threshold, we measured 50% paw withdrawal thresholds and thermal paw withdrawal latencies. Negative emotions were evaluated through the open field test, marble-burying test, sucrose preference test, and forced swimming test. Moreover, the conditional place preference test was conducted to measure the reward behavior in response to pain relief. Immunofluorescence staining, Western blotting, and qPCR were used to detect the activity of the VTADA-NAc reward circuit. Result The injection of CFA significantly lowered the pain threshold. As the pain persisted, the anxiety and depression-like behaviors escalated while the response to reward reduced. Meanwhile, the VTADA-NAc pathway was suppressed with pain chronification. However, activating DA neurons in VTA attenuated the effects induced by CFA. LEA could relieve chronic pain, negative emotions, and reward disorders, while also activating the VTADA-NAc pathway. In addition, LEA + SEA exhibited a more pronounced effect compared with LEA alone. Nevertheless, chemogenetic inhibition of DA neurons decreased the efficacy of LEA + SEA in the treatment of chronic pain and associated comorbidities. Conclusion Adding SEA to conventional LEA effectively alleviates negative emotions and chronic pain, potentially due to the activation of the VTADA-NAc reward neural circuit. Thus, LEA + SEA is a more effective treatment for hyperalgesia and associated negative emotions compared with LEA alone.
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Affiliation(s)
- Yanan Yang
- Department of Traditional Chinese Medicine, China Resources & Wugang General Hospital, Wuhan, China
| | - Xiali Wei
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Jun Tian
- Department of Rehabilitation, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ye Zhu
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
- Department of Rehabilitation, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shaohui Jia
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Qing Shu
- Department of Rehabilitation, Zhongnan Hospital of Wuhan University, Wuhan, China
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20
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Richardson BJ, Hamilton J, Roeder N, Thanos KZ, Marion M, Thanos PK. Fatty acid-binding protein 5 differentially impacts dopamine signaling independent of sex and environment. ADDICTION NEUROSCIENCE 2023; 8:100118. [PMID: 37664218 PMCID: PMC10470066 DOI: 10.1016/j.addicn.2023.100118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Epidermal/brain fatty acid-binding protein 5 (FABP5) plays an integral role in the intracellular trafficking of bioactive lipids/endocannabinoids and the subsequent initiation of cellular cascades affecting cannabinoid and dopamine (DA) systems. Social isolation (SI) and environmental enrichment (EE) during adolescence have been shown to impact DA signaling, and, specifically, DA transporter (DAT) and receptor levels of DA type 1 (D1) and 2 (D2); however, the relationship between FABP5, environment and DA signaling remains unclear. The present study quantified DAT and DA receptor levels in male/female FABP5-/- and FABP5+/+ mice raised in either SI or EE. Results showed that FABP5-/- mice had 6.09-8.81% greater D1 levels in striatal sub-regions of the caudal brain, independent of sex or environment. D1 levels were 8.03% greater only in the olfactory tubercle of enrichment-reared animals. In summary, these results supported that FABP5 plays an important function in regulating striatal DA signaling, and this may have important implications as a target with therapeutic potential for various psychiatric disorders.
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Affiliation(s)
- Brittany J. Richardson
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, 1021 Main Street, Buffalo, NY 14203-1016, USA
| | - John Hamilton
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, 1021 Main Street, Buffalo, NY 14203-1016, USA
- Department of Psychology, University at Buffalo, Buffalo, NY, USA
| | - Nicole Roeder
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, 1021 Main Street, Buffalo, NY 14203-1016, USA
- Department of Psychology, University at Buffalo, Buffalo, NY, USA
| | - Kyriaki Z. Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, 1021 Main Street, Buffalo, NY 14203-1016, USA
| | - Matthew Marion
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, 1021 Main Street, Buffalo, NY 14203-1016, USA
| | - Panayotis K. Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, 1021 Main Street, Buffalo, NY 14203-1016, USA
- Department of Psychology, University at Buffalo, Buffalo, NY, USA
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21
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Reumann D, Krauditsch C, Novatchkova M, Sozzi E, Wong SN, Zabolocki M, Priouret M, Doleschall B, Ritzau-Reid KI, Piber M, Morassut I, Fieseler C, Fiorenzano A, Stevens MM, Zimmer M, Bardy C, Parmar M, Knoblich JA. In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain-striatum-cortex assembloids. Nat Methods 2023; 20:2034-2047. [PMID: 38052989 PMCID: PMC10703680 DOI: 10.1038/s41592-023-02080-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 10/10/2023] [Indexed: 12/07/2023]
Abstract
Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson's disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson's disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain-striatum-cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.
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Affiliation(s)
- Daniel Reumann
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Vienna BioCenter, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Christian Krauditsch
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
| | - Maria Novatchkova
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
| | - Edoardo Sozzi
- Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Sakurako Nagumo Wong
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Vienna BioCenter, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Michael Zabolocki
- Laboratory for Human Neurophysiology and Genetics, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
- Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
| | - Marthe Priouret
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
| | - Balint Doleschall
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Vienna BioCenter, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Kaja I Ritzau-Reid
- Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, UK
| | - Marielle Piber
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Zebrafish Neurogenetics Unit, Institut Pasteur, Paris, France
| | - Ilaria Morassut
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Charles Fieseler
- Department of Neuroscience and Developmental Biology, University of Vienna, Vienna, Austria
| | - Alessandro Fiorenzano
- Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund Stem Cell Center, Lund University, Lund, Sweden
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics 'Adriano Buzzati Traverso' (IGB), CNR, Naples, Italy
| | - Molly M Stevens
- Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, UK
| | - Manuel Zimmer
- Department of Neuroscience and Developmental Biology, University of Vienna, Vienna, Austria
| | - Cedric Bardy
- Laboratory for Human Neurophysiology and Genetics, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
- Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
| | - Malin Parmar
- Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Jürgen A Knoblich
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria.
- Department of Neurology, Medical University of Vienna, Vienna, Austria.
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22
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Latagliata EC, Orsini C, Cabib S, Biagioni F, Fornai F, Puglisi-Allegra S. Prefrontal Dopamine in Flexible Adaptation to Environmental Changes: A Game for Two Players. Biomedicines 2023; 11:3189. [PMID: 38137410 PMCID: PMC10740496 DOI: 10.3390/biomedicines11123189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Deficits in cognitive flexibility have been characterized in affective, anxiety, and neurodegenerative disorders. This paper reviews data, mainly from studies on animal models, that support the existence of a cortical-striatal brain circuit modulated by dopamine (DA), playing a major role in cognitive/behavioral flexibility. Moreover, we reviewed clinical findings supporting misfunctioning of this circuit in Parkinson's disease that could be responsible for some important non-motoric symptoms. The reviewed findings point to a role of catecholaminergic transmission in the medial prefrontal cortex (mpFC) in modulating DA's availability in the nucleus accumbens (NAc), as well as a role of NAc DA in modulating the motivational value of natural and conditioned stimuli. The review section is accompanied by a preliminary experiment aimed at testing weather the extinction of a simple Pavlovian association fosters increased DA transmission in the mpFC and inhibition of DA transmission in the NAc.
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Affiliation(s)
| | - Cristina Orsini
- I.R.C.C.S. Fondazione Santa Lucia, 00143 Rome, Italy; (C.O.); (S.C.)
- Department of Psychology, Sapienza University of Rome, 00185 Rome, Italy
| | - Simona Cabib
- I.R.C.C.S. Fondazione Santa Lucia, 00143 Rome, Italy; (C.O.); (S.C.)
- Department of Psychology, Sapienza University of Rome, 00185 Rome, Italy
| | - Francesca Biagioni
- I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Italy; (F.B.); (F.F.)
| | - Francesco Fornai
- I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Italy; (F.B.); (F.F.)
- Department of Translational Research and New Technologies on Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
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23
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Hayashi D, Edwards C, Emond JA, Gilbert-Diamond D, Butt M, Rigby A, Masterson TD. What Is Food Noise? A Conceptual Model of Food Cue Reactivity. Nutrients 2023; 15:4809. [PMID: 38004203 PMCID: PMC10674813 DOI: 10.3390/nu15224809] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/14/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
As GLP-1 receptor agonists, like semaglutide, emerge as effective treatments for weight management, anecdotal reports from patients and clinicians alike point to a reduction in what has been colloquially termed "food noise", as patients report experiencing less rumination and obsessive preoccupation about food. In this narrative review, we discuss concepts used in studies to investigate human eating behavior that can help elucidate and define food noise, particularly food cue reactivity. We propose a conceptual model that summarizes the main factors that have been shown to determine the magnitude of the reactivity elicited by external and internal food cues and how these factors can affect short- and long-term behavioral and clinical outcomes. By integrating key research conducted in this field, the Cue-Influencer-Reactivity-Outcome (CIRO) model of food cue reactivity provides a framework that can be used in future research to design studies and interpret findings related to food noise and food cue reactivity.
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Affiliation(s)
- Daisuke Hayashi
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16801, USA (T.D.M.)
| | - Caitlyn Edwards
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16801, USA (T.D.M.)
| | - Jennifer A. Emond
- Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
| | - Diane Gilbert-Diamond
- Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
| | - Melissa Butt
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Andrea Rigby
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA
- Penn State Health, Milton S. Hershey Medical Center, Hershey, PA 17033, USA
| | - Travis D. Masterson
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16801, USA (T.D.M.)
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24
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Antón-Galindo E, Cabana-Domínguez J, Torrico B, Corominas R, Cormand B, Fernàndez-Castillo N. The pleiotropic contribution of genes in dopaminergic and serotonergic pathways to addiction and related behavioral traits. Front Psychiatry 2023; 14:1293663. [PMID: 37937232 PMCID: PMC10627163 DOI: 10.3389/fpsyt.2023.1293663] [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: 09/13/2023] [Accepted: 09/28/2023] [Indexed: 11/09/2023] Open
Abstract
Introduction Co-occurrence of substance use disorders (SUD) and other behavioral conditions, such as stress-related, aggressive or risk-taking behaviors, in the same individual has been frequently described. As dopamine (DA) and serotonin (5-HT) have been previously identified as key neurotransmitters for some of these phenotypes, we explored the genetic contribution of these pathways to SUD and these comorbid phenotypes in order to better understand the genetic relationship between them. Methods We tested the association of 275 dopaminergic genes and 176 serotonergic genes with these phenotypes by performing gene-based, gene-set and transcriptome-wide association studies in 11 genome-wide association studies (GWAS) datasets on SUD and related behaviors. Results At the gene-wide level, 68 DA and 27 5-HT genes were found to be associated with at least one GWAS on SUD or related behavior. Among them, six genes had a pleiotropic effect, being associated with at least three phenotypes: ADH1C, ARNTL, CHRNA3, HPRT1, HTR1B and DRD2. Additionally, we found nominal associations between the DA gene sets and SUD, opioid use disorder, antisocial behavior, irritability and neuroticism, and between the 5-HT-core gene set and neuroticism. Predicted gene expression correlates in brain were also found for 19 DA or 5-HT genes. Discussion Our study shows a pleiotropic contribution of dopaminergic and serotonergic genes to addiction and related behaviors such as anxiety, irritability, neuroticism and risk-taking behavior, highlighting a role for DA genes, which could explain, in part, the co-occurrence of these phenotypes.
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Affiliation(s)
- Ester Antón-Galindo
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Judit Cabana-Domínguez
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Mental Health, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Bàrbara Torrico
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Roser Corominas
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Bru Cormand
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Noèlia Fernàndez-Castillo
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
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25
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Kong D, Sun JX, Yang JQ, Li YS, Bi K, Zhang ZY, Wang KH, Luo HY, Zhu M, Xu Y. Ketogenic diet: a potential adjunctive treatment for substance use disorders. Front Nutr 2023; 10:1191903. [PMID: 37575322 PMCID: PMC10414993 DOI: 10.3389/fnut.2023.1191903] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/13/2023] [Indexed: 08/15/2023] Open
Abstract
Substance use disorders (SUD) can lead to serious health problems, and there is a great interest in developing new treatment methods to alleviate the impact of substance abuse. In recent years, the ketogenic diet (KD) has shown therapeutic benefits as a dietary therapy in a variety of neurological disorders. Recent studies suggest that KD can compensate for the glucose metabolism disorders caused by alcohol use disorder by increasing ketone metabolism, thereby reducing withdrawal symptoms and indicating the therapeutic potential of KD in SUD. Additionally, SUD often accompanies increased sugar intake, involving neural circuits and altered neuroplasticity similar to substance addiction, which may induce cross-sensitization and increased use of other abused substances. Reducing carbohydrate intake through KD may have a positive effect on this. Finally, SUD is often associated with mitochondrial damage, oxidative stress, inflammation, glia dysfunction, and gut microbial disorders, while KD may potentially reverse these abnormalities and serve a therapeutic role. Although there is much indirect evidence that KD has a positive effect on SUD, the small number of relevant studies and the fact that KD leads to side effects such as metabolic abnormalities, increased risk of malnutrition and gastrointestinal symptoms have led to the limitation of KD in the treatment of SUD. Here, we described the organismal disorders caused by SUD and the possible positive effects of KD, aiming to provide potential therapeutic directions for SUD.
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Affiliation(s)
- Deshenyue Kong
- General Hospital of Eastern Theater Command, Nanjing, China
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jia-xue Sun
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ji-qun Yang
- Third People’s Hospital of Kunming City/Drug Rehabilitation Hospital of Kunming City, Kunming, China
| | - Yuan-sen Li
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ke Bi
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zun-yue Zhang
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
| | - Kun-hua Wang
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
| | - Hua-you Luo
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Mei Zhu
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yu Xu
- General Hospital of Eastern Theater Command, Nanjing, China
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
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26
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Shao D, Jiang D, Huang Q, Ren S, Li J, Xiao J, Guan Y, Lai B, Zhao J, Xie F, Hua F. Brain glucose metabolism and dopamine transporter changes in rats with morphine-induced conditioned place preference. Addict Biol 2023; 28:e13277. [PMID: 37186440 DOI: 10.1111/adb.13277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/15/2022] [Accepted: 03/20/2023] [Indexed: 05/17/2023]
Abstract
Addiction to morphine is a chronic brain disease leading to compulsive abuse. Drug addiction animal models with and without conditioned place preference (CPP) training have been used to investigate cue-elicited drug craving. We used 18 F-fluorodeoxyglucose (18 F-FDG) and 11 C-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (11 C-CFT) micro-PET/CT scans to examine the regional changes in brain glucose metabolism and dopamine transporter (DAT) availability to study their relationship underlying drug memory in morphine-treated rat models with and without CPP. Standardized uptake value ratio (SUVr) of 18 F-FDG significantly decreased in the medial prefrontal cortex (mPFC) and cingulate with short-term morphine administration compared with the baseline condition. Voxelwise analysis indicated glucose metabolism alterations in the somatosensory cortex, hippocampus and cingulate in morphine-treated rats and in the striatum, thalamus, medial prefrontal cortex, primary motor cortex and many regions in the cortex in the CPP group compared with the baseline condition. Alterative glucose metabolism was also observed in the striatum, primary somatosensory cortex and some cortical regions in the CPP group compared with morphine alone group. DAT expression alterations were only observed in the long-term morphine compared with the short-term morphine group. This study shows that cerebral glucose metabolism significantly altered during morphine administration and CPP process mainly in the mPFC, striatum and hippocampus, which indicates that the function of these brain regions is involved in cue-induced craving and memory retrieval.
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Affiliation(s)
- Da Shao
- Research Center of Translational Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Donglang Jiang
- Department of Nuclear Medcine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Qi Huang
- Department of Nuclear Medcine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Shuhua Ren
- Department of Nuclear Medcine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Junpeng Li
- Department of Nuclear Medcine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
- Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianfei Xiao
- Department of Nuclear Medcine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Yihui Guan
- Department of Nuclear Medcine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Bin Lai
- Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Jun Zhao
- Department of Nuclear Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fang Xie
- Department of Nuclear Medcine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Fengchun Hua
- Department of Nuclear Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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27
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Huang B, Wu Y, Li C, Tang Q, Zhang Y. Molecular basis and mechanism of action of Albizia julibrissin in depression treatment and clinical application of its formulae. CHINESE HERBAL MEDICINES 2023; 15:201-213. [PMID: 37265761 PMCID: PMC10230641 DOI: 10.1016/j.chmed.2022.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 07/21/2022] [Accepted: 10/11/2022] [Indexed: 03/17/2023] Open
Abstract
Albizzia julibrissin is empirically used as an antidepressant in clinical practice. Preclinical studies have indicated that its total extracts or bioactive constituents exerted antidepressant-like responses in animal models, providing the molecular basis to reveal its underlying mechanism of action. While attempts have been made to understand the antidepressant effect of A. julibrissin, many fundamental questions regarding its mechanism of action remain to be addressed at the molecular and systems levels. In this review, we conclusively discussed the mechanism of action of A. julibrissin and A. julibrissin formulae by reviewing recent preclinical and clinical studies conducted by using depressive animal models and depressive patients. Several representative bioactive constituents and formulae were highlighted as examples, and their mechanisms of action were discussed. In addition, some representative A. julibrissin formulae that have been shown to be compatible with conventional antidepressants in clinical practice were also reviewed. Furthermore, we discussed the future research directions to reveal the underlying mechanism of A. julibrissin at the molecular and systems levels in depression treatment. The integrated study using both the molecular and systematic approaches is required not only for improving our understanding of its molecular basis and mechanisms of action, but also for providing a way to discover novel agents or approaches for the effective and systematic treatment of depression.
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Affiliation(s)
- Bishan Huang
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China
| | - Yingyao Wu
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China
| | - Chan Li
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China
| | - Qingfa Tang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yuanwei Zhang
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China
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28
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Abstract
The midbrain dopamine (mDA) system is composed of molecularly and functionally distinct neuron subtypes that mediate specific behaviours and are linked to various brain diseases. Considerable progress has been made in identifying mDA neuron subtypes, and recent work has begun to unveil how these neuronal subtypes develop and organize into functional brain structures. This progress is important for further understanding the disparate physiological functions of mDA neurons and their selective vulnerability in disease, and will ultimately accelerate therapy development. This Review discusses recent advances in our understanding of molecularly defined mDA neuron subtypes and their circuits, ranging from early developmental events, such as neuron migration and axon guidance, to their wiring and function, and future implications for therapeutic strategies.
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29
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Collins V, Bornhoft KN, Wolff A, Sinha S, Saunders BT. Hierarchical cue control of cocaine seeking in the face of cost. Psychopharmacology (Berl) 2023; 240:461-476. [PMID: 36069951 PMCID: PMC10131580 DOI: 10.1007/s00213-022-06218-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 08/22/2022] [Indexed: 12/30/2022]
Abstract
RATIONALE Addiction is characterized by intermittent drug seeking despite rising costs. This behavior is heavily influenced by environmental stimuli that signal drug availability and reinforce drug seeking. OBJECTIVE To establish the relationship between three key aspects of human drug use in rats: the intermittent, binge nature of drug intake, the motivational conflict of drug seeking in the face of escalating negative costs, and the ability of different drug cues to interact to modulate relapse. METHODS Male and female rats were trained to self-administer cocaine on an intermittent access schedule, where brief drug-availability states were signaled by a shift in the ambient lighting of the environment, and cocaine infusions were signaled by a separate proximal discrete cue. Rats then went through a conflict procedure, where foot shock intensity associated with cocaine seeking was escalated until intake was suppressed. We then completed relapse tests where the drug-delivery cue was noncontingently presented alone, or in the context of dynamic drug-availability state transitions. RESULTS Intermittent access spurred psychomotor sensitization and binge-like cocaine intake. The intensity of binge-like drug taking during training was predictive of later drug seeking despite escalating costs during conflict. In relapse tests, the ability of a proximal discrete drug cue to trigger relapse was gated by the presence of a global cue signaling drug-availability state transitions. CONCLUSIONS Our results suggest that the pattern of drug intake plays a role in many features of addiction, including modifying an individual's willingness to endure high costs associated with drug seeking. Furthermore, our studies indicate that drug-related sensory information can be hierarchically organized to exert a dynamic modulating influence on drug-seeking motivation.
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Affiliation(s)
- Val Collins
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Medical Discovery Team On Addiction, University of Minnesota, Minneapolis, MN, USA
- University of California, San Francisco, CA, USA
| | - Kaisa N Bornhoft
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Medical Discovery Team On Addiction, University of Minnesota, Minneapolis, MN, USA
| | - Amy Wolff
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Medical Discovery Team On Addiction, University of Minnesota, Minneapolis, MN, USA
| | - Sonal Sinha
- Johns Hopkins University, Baltimore, MD, USA
| | - Benjamin T Saunders
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
- Medical Discovery Team On Addiction, University of Minnesota, Minneapolis, MN, USA.
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30
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Olasore HSA, Osuntoki AA, Magbagbeola OA, Awesu ARB, Olashore AA. Association of Dopamine Transporter Gene (DAT1) 40 bp 3′ UTR VNTR Polymorphism (rs28363170) and Cannabis Use Disorder. SUBSTANCE ABUSE: RESEARCH AND TREATMENT 2023; 17:11782218231163696. [PMID: 37020726 PMCID: PMC10068503 DOI: 10.1177/11782218231163696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 02/27/2023] [Indexed: 04/03/2023]
Abstract
Introduction: Cannabis remains the most widely used illicit drug among Nigerians, often associated with psychiatric disorders. Since genetic predisposition has been implicated in substance use disorders, we, therefore, aimed at finding out the relationship between dopamine transporter gene (DAT1) polymorphism and cannabis use disorder. Methods: We recruited 104 patients from a tertiary psychiatric facility in Lagos, Nigeria, who were diagnosed with cannabis use disorder according to ICD-10 and 96 non-smokers as a comparative group. The smokers were screened with Cannabis Use Disorder Identification Test (CUDIT), and cannabis dependence was assessed with the Severity of Dependence Scale (SDS). Genotyping was carried out for the 40 bp 3′ UTR VNTR of the DAT1 (rs28363170). Results: The frequencies of 9R/9R, 9R/10R, 10R/10R among non-smokers and smokers were 14 (14.3%), 25 (26.2%), 57 (59.5%) and 17 (16.3%), 54 (51.9%), 33 (31.7%) respectively. The genotype distribution was in Hardy Weinberg equilibrium (HWE) only in the smokers’ population (χ² = 1.896, P = .166). Individuals with the 10R allele were almost twice as likely as the 9R carriers to smoke cannabis (OR = 1.915, 95% CI: 1.225-2.995). However, this polymorphism was not associated with the quantity of cannabis smoked, age at onset of smoking, CUDIT, and SDS scores. Conclusion: The DAT VNTR polymorphism was associated with cannabis smoking but not cannabis use disorder.
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Affiliation(s)
- Holiness SA Olasore
- Department of Biochemistry, College of Medicine of the University of Lagos, Idi Araba, Lagos, Nigeria
| | - Akinniyi A Osuntoki
- Department of Biochemistry, College of Medicine of the University of Lagos, Idi Araba, Lagos, Nigeria
| | - Olubunmi A Magbagbeola
- Department of Biochemistry, College of Medicine of the University of Lagos, Idi Araba, Lagos, Nigeria
| | | | - Anthony A Olashore
- Department of Psychiatry, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
- Department of Psychiatry, University of Botswana, Gaborone, Botswana
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31
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Park JH, Yoo SY, Park HY, Choi JS. Resting-state heart rate variability, level of stress and resilience in internet gaming disorder and alcohol use disorder. Front Pharmacol 2023; 14:1152819. [PMID: 37205906 PMCID: PMC10188983 DOI: 10.3389/fphar.2023.1152819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 04/20/2023] [Indexed: 05/21/2023] Open
Abstract
Stress and resilience are involved in the pathophysiology of addictive disorders, and heart rate variability (HRV) is an index of an individual's global capability to regulate psychological responses. In this study, we aimed to identify transdiagnostic and disorder-specific markers in people with addictive disorders by analyzing resting-state HRV and associations with the levels of stress and resilience. We compared relevant data between patients with internet gaming disorder (IGD) and/or alcohol use disorder (AUD) and healthy controls (HCs). In all, 163 adults aged 18-35 years (53 with IGD, 49 with AUD, 61 HCs) participated. The levels of stress and resilience were measured using the Psychosocial Wellbeing Index and the Connor-Davidson Resilience Scale, respectively. The HRV was obtained from each participant during a 5 min resting-state. The IGD and AUD patients exhibited increased levels of stress and decreased resilience compared to the HCs. Patients with either addictive disorder exhibited a lower standard deviation of the normal-to-normal beat interval (SDNN) index [SDNNi] compared to HCs even after adjusting for clinical variables such as depression, anxiety, and impulsivity. In multiple comparison tests among the three groups, the AUD group had lower HRV than HCs, but no differences were observed among the groups after adjusting for the clinical variables. The HRV indices were correlated with the levels of stress, resilience, and disease severity. In conclusion, IGD and AUD patients exhibit lower HRV as indicated by the SDNNi compared to HCs, revealing their vulnerability to stress as well as a common transdiagnostic marker of addiction.
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Affiliation(s)
- Jong Hu Park
- Department of Psychiatry, Seoul National University Hospital, Seoul, South Korea
| | - So Young Yoo
- Department of Psychiatry, SMG-SNU Boramae Medical Center, Seoul, South Korea
| | - Hye Yoon Park
- Department of Psychiatry, Seoul National University Hospital, Seoul, South Korea
- *Correspondence: Hye Yoon Park, ; Jung-Seok Choi,
| | - Jung-Seok Choi
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- *Correspondence: Hye Yoon Park, ; Jung-Seok Choi,
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Ceccanti M, Blum K, Bowirrat A, Dennen CA, Braverman ER, Baron D, Mclaughlin T, Giordano J, Gupta A, Downs BW, Bagchi D, Barh D, Elman I, Thanos PK, Badgaiyan RD, Edwards D, Gold MS. Future Newborns with Opioid-Induced Neonatal Abstinence Syndrome (NAS) Could Be Assessed with the Genetic Addiction Risk Severity (GARS) Test and Potentially Treated Using Precision Amino-Acid Enkephalinase Inhibition Therapy (KB220) as a Frontline Modality Instead of Potent Opioids. J Pers Med 2022; 12:2015. [PMID: 36556236 PMCID: PMC9782293 DOI: 10.3390/jpm12122015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/14/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
In this nonsystematic review and opinion, including articles primarily selected from PubMed, we examine the pharmacological and nonpharmacological treatments of neonatal abstinence syndrome (NAS) in order to craft a reasonable opinion to help forge a paradigm shift in the treatment and prevention of primarily opioid-induced NAS. Newborns of individuals who use illicit and licit substances during pregnancy are at risk for withdrawal, also known as NAS. In the US, the reported prevalence of NAS has increased from 4.0 per 1000 hospital births in 2010 to 7.3 per 1000 hospital births in 2017, which is an 82% increase. The management of NAS is varied and involves a combination of nonpharmacologic and pharmacologic therapy. The preferred first-line pharmacological treatment for NAS is opioid therapy, specifically morphine, and the goal is the short-term improvement in NAS symptomatology. Nonpharmacological therapies are individualized and typically focus on general care measures, the newborn-parent/caregiver relationship, the environment, and feeding. When used appropriately, nonpharmacologic therapies can help newborns with NAS avoid or reduce the amount of pharmacologic therapy required and the length of hospitalization. In addition, genetic polymorphisms of the catechol-o-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genes appear to affect the length of stay and the need for pharmacotherapy in newborns with prenatal opioid exposure. Therefore, based on this extensive literature and additional research, this team of coauthors suggests that, in the future, in addition to the current nonpharmacological therapies, patients with opioid-induced NAS should undergo genetic assessment (i.e., the genetic addiction risk severity (GARS) test), which can subsequently be used to guide DNA-directed precision amino-acid enkephalinase inhibition (KB220) therapy as a frontline modality instead of potent opioids.
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Affiliation(s)
- Mauro Ceccanti
- Società Italiana per il Trattamento dell’Alcolismo e le sue Complicanze (SITAC), ASL Roma1, Sapienza University of Rome, 00185 Rome, Italy
| | - Kenneth Blum
- The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, USA
- Division of Addiction Research & Education, Center for Mental Health & Sports, Exercise and Global Mental Health, Western University Health Sciences, Pomona, CA 91766, USA
- Institute of Psychology, ELTE Eötvös Loránd University, Egyetem tér 1-3, H-1053 Budapest, Hungary
- Department of Psychiatry, School of Medicine, University of Vermont, Burlington, VT 05405, USA
- Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Centre, Dayton, OH 45324, USA
- Reward Deficiency Clinics of America, Austin, TX 78701, USA
- Center for Genomics and Applied Gene Technology, Institute of Integrative Omics and applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West Bengal 721172, India
- Department of Precision Behavioral Management, Transplicegen Therapeutics, Inc., LLC., Austin, TX 78701, USA
- Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel 40700, Israel
| | - Abdalla Bowirrat
- Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel 40700, Israel
| | - Catherine A. Dennen
- Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA 19107, USA
| | - Eric R. Braverman
- The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, USA
| | - David Baron
- Division of Addiction Research & Education, Center for Mental Health & Sports, Exercise and Global Mental Health, Western University Health Sciences, Pomona, CA 91766, USA
| | | | - John Giordano
- The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, USA
- Ketamine Infusion Clinic of South Florida, Pompano Beach, FL 33062, USA
| | - Ashim Gupta
- Future Biologics, Lawrenceville, GA 30043, USA
| | - Bernard W. Downs
- The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, USA
| | - Debasis Bagchi
- The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, USA
- Department of Pharmaceutical Sciences, Southern University College of Pharmacy, Houston, TX 77004, USA
| | - Debmalya Barh
- Center for Genomics and Applied Gene Technology, Institute of Integrative Omics and applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West Bengal 721172, India
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil
| | - Igor Elman
- Center for Pain and the Brain (PAIN Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children’s Hospital, Harvard School of Medicine, Boston, MA 02115, USA
| | - Panayotis K. Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA
| | - Rajendra D. Badgaiyan
- Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Medical Center, San Antonio, TX 78229, USA
| | - Drew Edwards
- Neurogenesis Project, Jacksonville, FL 32223, USA
| | - Mark S. Gold
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
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GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders. Biomedicines 2022; 10:biomedicines10102552. [PMID: 36289814 PMCID: PMC9599444 DOI: 10.3390/biomedicines10102552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/05/2022] [Accepted: 10/09/2022] [Indexed: 11/16/2022] Open
Abstract
Substance use disorders (SUDs) are chronic, lifelong disorders that have serious consequences. Repeated substance use alters brain function. G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed widely in the brain, including the reward system, and regulate neuronal excitability. Functional GIRK channels are identified as heterotetramers of GIRK subunits (GIRK1–4). The GIRK1, GIRK2, and GIRK3 subunits are mainly expressed in rodent brain regions, and various addictive substances act on the brain through GIRK channels. Studies with animals (knockout and missense mutation animals) and humans have demonstrated the involvement of GIRK channels in the effects of addictive substances. Additionally, GIRK channel blockers affect behavioral responses to addictive substances. Thus, GIRK channels play a key role in SUDs, and GIRK channel modulators may be candidate medications. Ifenprodil is a GIRK channel blocker that does not have serious side effects. Two clinical trials were conducted to investigate the effects of ifenprodil in patients with alcohol or methamphetamine use disorder. Although the number of participants was relatively low, evidence of its safety and efficacy was found. The present review discusses the potential of GIRK channel modulators as possible medications for addiction. Therapeutic agents that target GIRK channels may be promising for the treatment of SUDs.
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Yuwong Wanyu B, Emégam Kouémou N, Sotoing Taiwe G, Temkou Ngoupaye G, Tamanji Ndzweng L, Lambou Fotio A, Nguepi Dongmo MS, Ngo Bum E. Dichrocephala integrifolia Aqueous Extract Antagonises Chronic and Binges Ethanol Feeding-Induced Memory Dysfunctions: Insights into Antioxidant and Anti-Inflammatory Mechanisms. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:1620816. [PMID: 36110196 PMCID: PMC9470300 DOI: 10.1155/2022/1620816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 08/07/2022] [Indexed: 11/28/2022]
Abstract
Ethanol consumption is widely accepted despite its addictive properties and its mind-altering effects. This study aimed to assess the effects of Dichrocephala integrifolia against, memory impairment, on a mouse model of chronic and binges ethanol feeding. Mice were divided, into groups of 8 animals each, and received distilled water, Dichrocephala integrifolia aqueous extract (25; 50; 100; or 200 mg/kg) or memantine (200 mg/kg) once a day, while fe, with Lieber-DeCarli control (sham group only) or Lieber-DeCarli ethanol diet ad libitum for 28 days. The Y maze and the novel object recognition (NOR) tests were used to evaluate spatial short-term and recognition memory, respectively. Malondialdehyde, nitric oxide, glutathione levels, and proinflammatory cytokines (Il-1β, TNF-α, and Il-6) were evaluated in brain homogenates following behavioral assessments. The results showed that chronic ethanol administration in mice was associated with a significant (p < 0.001) reduction in the spontaneous alternation percentage and the discrimination index, in the Y maze and the NOR tests, respectively. It significantly (p < 0.01) increased oxidative stress and inflammation markers levels in the brain. Dichrocephala integrifolia (100 and 200 mg/kg) as well as memantine (200 mg/kg) significantly (p < 0.001) increased the percentage of spontaneous alternation and the discrimination index, in the Y maze and NOR tests, respectively. Dichrocephala integrifolia (100 and 200 mg/kg) likewise memantine (200 mg/kg) significantly (p < 0.01) alleviated ethanol-induced increase, in the brain malondialdehyde level, nitric oxide, Il-1β, TNF-α, and Il-6. From these findings, it can be concluded that Dichrocephala integrifolia counteracted memory impairment, oxidative stress, and neuroinflammation induced by chronic ethanol consumption in mice.
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Affiliation(s)
- Bertrand Yuwong Wanyu
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon
| | - Nadège Emégam Kouémou
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon
| | - Germain Sotoing Taiwe
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon
| | - Gwladys Temkou Ngoupaye
- Department of Animal Biology, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon
| | - Linda Tamanji Ndzweng
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon
| | - Agathe Lambou Fotio
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon
| | | | - Elisabeth Ngo Bum
- Department of Biological Sciences, Faculty of Science, University of Maroua, P.O. Box 52, Maroua, Cameroon
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Stokes C, Pino JA, Hagan DW, Torres GE, Phelps EA, Horenstein NA, Papke RL. Betel quid: New insights into an ancient addiction. Addict Biol 2022; 27:e13223. [PMID: 36001424 PMCID: PMC9552247 DOI: 10.1111/adb.13223] [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: 07/20/2022] [Accepted: 07/22/2022] [Indexed: 11/27/2022]
Abstract
The use of areca nuts (areca) in the form of betel quids constitutes the fourth most common addiction in the world, associated with high risk for oral disease and cancer. Areca is a complex natural product, making it difficult to identify specific components associated with the addictive and carcinogenic properties. It is commonly believed that the muscarinic agonist arecoline is at the core of the addiction. However, muscarinic receptor activation is not generally believed to support drug-taking behaviour. Subjective accounts of areca use include descriptions of both sedative and stimulatory effects, consistent with the presence of multiple psychoactive agents. We have previously reported partial agonism of α4-containing nicotinic acetylcholine receptors by arecoline and subsequent inhibition of those receptors by whole areca broth. In the present study, we report the inhibition of nicotinic acetylcholine receptors and other types of neurotransmitter receptors with compounds of high molecular weight in areca and the ability of low molecular weight areca extract to activate GABA and glutamate receptors. We confirm the presence of a high concentration of GABA and glutamate in areca. Additionally, data also indicate the presence of a dopamine and serotonin transporter blocking activity in areca that could account for the reported stimulant and antidepressant activity. Our data suggest that toxic elements of high molecular weight may contribute to the oral health liability of betel quid use, while two distinct low molecular weight components may provide elements of reward, and the nicotinic activity of arecoline contributes to the physical dependence of addiction.
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Affiliation(s)
- Clare Stokes
- Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267 Gainesville, FL 32610
| | - Jose A. Pino
- Department of Medicine, School of Medicine, University of Atacama, Copiapó, Chile
| | - D. Walker Hagan
- Department of Biomedical Engineering University of Florida, PO Box 100267 Gainesville, FL 32611
| | - Gonzalo E. Torres
- Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, NY 10031
| | - Edward A. Phelps
- Department of Biomedical Engineering University of Florida, PO Box 100267 Gainesville, FL 32611
| | - Nicole A. Horenstein
- Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL 32611-7200
| | - Roger L. Papke
- Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267 Gainesville, FL 32610
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36
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Huang B, Liu H, Wu Y, Li C, Tang Q, Zhang YW. Two Lignan Glycosides from Albizia julibrissin Durazz. Noncompetitively Inhibit Serotonin Transporter. Pharmaceuticals (Basel) 2022; 15:ph15030344. [PMID: 35337141 PMCID: PMC8954383 DOI: 10.3390/ph15030344] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 12/11/2022] Open
Abstract
Albizia julibrissin Durazz. is one of the most common herbs used for depression and anxiety treatment, but its molecular basis and mechanism of action as an antidepressant or anxiolytic drug are not understood. In this study, we separated and identified two lignan glycosides that inhibit serotonin transporter (SERT) noncompetitively by decreasing Vmax with little change in Km for its fluorescence substrate. In addition, treatment with lignan glycosides did not alter total and cell surface expression levels of the transporter protein. The two compounds decreased the accessibility of a cysteine residue placed in the extracellular substrate permeation pathway by inducing a conformational shift toward an outward-closed state of SERT. These results are consistent with molecular docking for the association of the lignan glycosides to the allosteric site in SERT. The present work supports the proposal that these compounds act on SERT by a novel underlying mechanism of action different from that of conventional antidepressant drugs.
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Affiliation(s)
- Bishan Huang
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China; (B.H.); (H.L.); (Y.W.); (C.L.)
| | - Hanhe Liu
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China; (B.H.); (H.L.); (Y.W.); (C.L.)
| | - Yingyao Wu
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China; (B.H.); (H.L.); (Y.W.); (C.L.)
| | - Chan Li
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China; (B.H.); (H.L.); (Y.W.); (C.L.)
| | - Qingfa Tang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China;
- Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou 510515, China
| | - Yuan-Wei Zhang
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China; (B.H.); (H.L.); (Y.W.); (C.L.)
- Correspondence:
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