|
1
|
Feng Y, Jiang X, Liu W, Lu H. The location, physiology, pathology of hippocampus Melatonin MT 2 receptor and MT 2-selective modulators. Eur J Med Chem 2023; 262:115888. [PMID: 37866336 DOI: 10.1016/j.ejmech.2023.115888] [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: 08/27/2023] [Revised: 10/06/2023] [Accepted: 10/17/2023] [Indexed: 10/24/2023]
Abstract
Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into the cerebrospinal fluid (CSF) of the third ventricle (3rdv), where it undergoes rapid absorption by surrounding tissues to exert its physiological function. The hippocampus, a vital structure in the limbic system adjacent to the ventricles, plays a pivotal role in emotional response and memory formation. Melatonin MT1 and MT2 receptors are G protein-coupled receptors (GPCRs) that primarily mediate melatonin's receptor-dependent effects. In comparison to the MT1 receptor, the widely expressed MT2 receptor is crucial for mediating melatonin's biological functions within the hippocampus. Specifically, MT2 receptor is implicated in hippocampal synaptic plasticity and memory processes, as well as neurogenesis and axogenesis. Numerous studies have demonstrated the involvement of MT2 receptors in the pathophysiology and pharmacology of Alzheimer's disease, depression, and epilepsy. This review focuses on the anatomical localization of MT2 receptor in the hippocampus, their physiological function in this region, and their signal transduction and pharmacological roles in neurological disorders. Additionally, we conducted a comprehensive review of MT2 receptor ligands used in psychopharmacology and other MT2-selective ligands over recent years. Ultimately, we provide an outlook on future research for selective MT2 receptor drug candidates.
Collapse
Affiliation(s)
- Yueqin Feng
- Department of Ultrasound, the First Affiliated Hospital of China Medical University, Shenyang, PR China
| | - Xiaowen Jiang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Wenwu Liu
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, PR China
| | - Hongyuan Lu
- Department of Clinical Pharmacology, China Medical University, Shenyang, PR China.
| |
Collapse
|
|
2
|
Munley KM, Han Y, Lansing MX, Demas GE. Winter madness: Melatonin as a neuroendocrine regulator of seasonal aggression. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2022; 337:873-889. [PMID: 35451566 PMCID: PMC9587138 DOI: 10.1002/jez.2601] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/16/2022] [Accepted: 04/07/2022] [Indexed: 12/25/2022]
Abstract
Individuals of virtually all vertebrate species are exposed to annual fluctuations in the deterioration and renewal of their environments. As such, organisms have evolved to restrict energetically expensive processes and activities to a specific time of the year. Thus, the precise timing of physiology and behavior is critical for individual reproductive success and subsequent fitness. Although the majority of research on seasonality has focused on seasonal reproduction, pronounced fluctuations in other non-reproductive social behaviors, including agonistic behaviors (e.g., aggression), also occur. To date, most studies that have investigated the neuroendocrine mechanisms underlying seasonal aggression have focused on the role of photoperiod (i.e., day length); prior findings have demonstrated that some seasonally breeding species housed in short "winter-like" photoperiods display increased aggression compared with those housed in long "summer-like" photoperiods, despite inhibited reproduction and low gonadal steroid levels. While fewer studies have examined how the hormonal correlates of environmental cues regulate seasonal aggression, our previous work suggests that the pineal hormone melatonin acts to increase non-breeding aggression in Siberian hamsters (Phodopus sungorus) by altering steroid hormone secretion. This review addresses the physiological and cellular mechanisms underlying seasonal plasticity in aggressive and non-aggressive social behaviors, including a key role for melatonin in facilitating a "neuroendocrine switch" to alternative physiological mechanisms of aggression across the annual cycle. Collectively, these studies highlight novel and important mechanisms by which melatonin regulates aggressive behavior in vertebrates and provide a more comprehensive understanding of the neuroendocrine bases of seasonal social behaviors broadly.
Collapse
Affiliation(s)
- Kathleen M. Munley
- Department of Biology and Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, IN 47405, USA
| | - Yuqi Han
- Department of Biology and Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, IN 47405, USA
| | - Matt X. Lansing
- Department of Biology and Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, IN 47405, USA
| | - Gregory E. Demas
- Department of Biology and Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, IN 47405, USA
| |
Collapse
|
|
3
|
Barbosa-Méndez S, Perez-Sánchez G, Salazar-Juárez A. Agomelatine decreases cocaine-induced locomotor sensitisation and dopamine release in rats. World J Biol Psychiatry 2022; 24:400-413. [PMID: 36097970 DOI: 10.1080/15622975.2022.2123954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
BACKGROUND Agomelatine is a melatoninergic antidepressant approved to treat the major depressive disorder. Agomelatine exerts its behavioural, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors and the blockade of 5-HT2B and 5-HT2C serotonin receptors. Some studies have reported that the activation of the MT1 and MT2 melatonin receptors decreased cocaine-induced locomotor activity and cocaine self-administration. These findings from another study showed that agomelatine decreased alcohol consumption. This study aimed to evaluate the effects of agomelatine administration on cocaine-induced behavioural (cocaine-induced locomotor activity and cocaine-induced locomotor sensitisation) and neurochemical (dopamine levels) effects. METHODS Male Wistar rats (250-280 g) received cocaine (10 mg/kg) during the induction and expression of locomotor sensitisation. Agomelatine (10 mg/kg) was administered 30 minutes before cocaine. After each treatment, locomotor activity was recorded for 30 minutes. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with agomelatine and cocaine. Luzindole (30 mg/kg) was administered to block the agomelatine effect. RESULTS In this study, we found that agomelatine decreased cocaine-induced locomotor activity and the induction and expression of locomotor sensitisation. In addition, agomelatine decreased cocaine-induced dopamine levels. Luzindole blocked the agomelatine-induced decrease in the expression of locomotor sensitisation in rats. CONCLUSION Our results suggest (1) that agomelatine showed efficacy in decreasing cocaine psychostimulant effects and (2) that agomelatine can be a useful therapeutic agent to reduce cocaine abuse.
Collapse
Affiliation(s)
- Susana Barbosa-Méndez
- Subdirección de Investigaciones Clínicas. Laboratorio de Neurofarmacología Conductual, Microcirugía y Terapéutica Experimental, Ciudad de Mexico, Mexico
| | - Gilberto Perez-Sánchez
- Dirección de Neurociencias, Laboratorio de Psicoinmunología. Instituto Nacional de Psiquiatría, Ciudad de México, México
| | - Alberto Salazar-Juárez
- Subdirección de Investigaciones Clínicas. Laboratorio de Neurofarmacología Conductual, Microcirugía y Terapéutica Experimental, Ciudad de Mexico, Mexico
| |
Collapse
|
|
4
|
Munley KM, Dutta S, Jasnow AM, Demas GE. Adrenal MT 1 melatonin receptor expression is linked with seasonal variation in social behavior in male Siberian hamsters. Horm Behav 2022; 138:105099. [PMID: 34920297 PMCID: PMC8847318 DOI: 10.1016/j.yhbeh.2021.105099] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/10/2021] [Accepted: 11/24/2021] [Indexed: 02/03/2023]
Abstract
Many animals exhibit pronounced changes in physiology and behavior on a seasonal basis, and these adaptations have evolved to promote survival and reproductive success. While the neuroendocrine pathways mediating seasonal reproduction are well-studied, far less is known about the mechanisms underlying seasonal changes in social behavior, particularly outside of the context of the breeding season. Our previous work suggests that seasonal changes in melatonin secretion are important in regulating aggression in Siberian hamsters (Phodopus sungorus); it is unclear, however, how melatonin acts via its receptors to modulate seasonal variation in social behavior. In this study, we infused a MT1 melatonin receptor-expressing (MT1) or control (CON) lentivirus into the adrenal glands of male Siberian hamsters. We then housed hamsters in long-day (LD) or short-day (SD) photoperiods, administered timed melatonin or control injections, and quantified aggressive and non-aggressive social behaviors (e.g., investigation, self-grooming) following 10 weeks of treatment. LD hamsters infused with the MT1 lentivirus had significantly higher adrenal mt1 expression than LD CON hamsters, as determined via quantitative PCR. While melatonin administration was necessary to induce SD-like reductions in body and relative reproductive mass, only LD hamsters infused with the MT1 lentivirus displayed SD-like changes in social behavior, including increased aggression and decreased investigation and grooming. In addition, SD CON and LD hamsters infused with the MT1 lentivirus exhibited similar relationships between adrenal mt1 expression and aggressive behavior. Together, our findings suggest a role for adrenal MT1 receptor signaling in regulating behavior, but not energetics or reproduction in seasonally breeding species.
Collapse
Affiliation(s)
- Kathleen M Munley
- Department of Biology and Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, IN 47405, USA.
| | - Sohini Dutta
- Department of Psychological Sciences, Kent State University, Kent, OH 44240, USA; Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Aaron M Jasnow
- Department of Psychological Sciences, Kent State University, Kent, OH 44240, USA; Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Gregory E Demas
- Department of Biology and Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, IN 47405, USA
| |
Collapse
|
|
5
|
Alghamdi BS, Alshehri FS. Melatonin Blocks Morphine-Induced Place Preference: Involvement of GLT-1, NF-κB, BDNF, and CREB in the Nucleus Accumbens. Front Behav Neurosci 2021; 15:762297. [PMID: 34720901 PMCID: PMC8551802 DOI: 10.3389/fnbeh.2021.762297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 09/28/2021] [Indexed: 12/27/2022] Open
Abstract
Opioid addiction remains a widespread issue despite continuous attempts by the FDA to help maintain abstinence. Melatonin is a neurohormone considered to be involved only in the neuroendocrine and reproductive systems; however, recent reports have demonstrated its potential to attenuate drug addiction and dependence. Cumulative studies have suggested that melatonin can attenuate the rewarding effects of several drugs of abuse, including opioids. This study aimed to investigate the effect of melatonin (50 mg/kg) on morphine (5 mg/kg) to produce place preference. We also investigated the effect of melatonin and morphine on the expression of GLT-1, BDNF, NF-κB, and CREB within the nucleus accumbens. Male Wistar rats were divided into control, morphine, melatonin, and the morphine + melatonin groups. The study involved a two-phase habituation phase from day 1 to day 3 and an acquisition phase from day 5 to day 14. The conditioned place preference (CPP) score, distance traveled, resting time, ambulatory count, and total activity count were measured for all animals. Rats that received morphine showed a significant increase in CPP score compared to those in the control group. Morphine treatment reduced the mRNA expression of GLT-1, BDNF, and CREB and increased that of NF-κB. However, melatonin treatment administered 30 min before morphine treatment attenuated morphine place preference and reversed GLT-1, BDNF, NF-κB, and CREB expression levels. In conclusion, the study results indicate, for the first time, the new potential targets of melatonin in modulating morphine-induced CPP.
Collapse
Affiliation(s)
- Badrah S Alghamdi
- Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fahad S Alshehri
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| |
Collapse
|
|
6
|
Thomson DM, Mitchell EJ, Openshaw RL, Pratt JA, Morris BJ. Mice lacking melatonin MT2 receptors exhibit attentional deficits, anxiety and enhanced social interaction. J Psychopharmacol 2021; 35:1265-1276. [PMID: 34304635 PMCID: PMC8521347 DOI: 10.1177/02698811211032439] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Aside from regulating circadian rhythms, melatonin also affects cognitive processes, such as alertness, and modulates the brain circuitry underlying psychiatric diseases, such as depression, schizophrenia and bipolar disorder, via mechanisms that are not fully clear. In particular, while melatonin MT1 receptors are thought primarily to mediate the circadian effects of the hormone, the contribution of the MT2 receptor to melatonin actions remains enigmatic. AIMS To characterise the contribution of MT2 receptors to melatonin's effects on cognition and anxiety/sociability. METHODS Mice with a genetic deletion of the MT2 receptor, encoded by the Mtnr1b gene, were compared with wild-type littermates for performance in a translational touchscreen version of the continuous performance task (CPT) to assess attentional processes and then monitored over 3 days in an ethological home-cage surveillance system. RESULTS Mtnr1b knockout (KO) mice were able to perform at relatively normal levels in the CPT. However, they showed consistent evidence of more liberal/risky responding strategies relative to control mice, with increases in hit rates and false alarm rates, which were maintained even when the cognitive demands of the task were increased. Assessment in the home-cage monitoring system revealed that female Mtnr1b KO mice have increased anxiety levels, whereas male Mtnr1b KO mice show increased sociability. CONCLUSIONS The results confirm that the MT2 receptor plays a role in cognition and also modulates anxiety and social interactions. These data provide new insights into the functions of endogenous melatonin and will inform future drug development strategies focussed on the MT2 receptor.
Collapse
Affiliation(s)
- David M Thomson
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Emma J Mitchell
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Rebecca L Openshaw
- Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Judith A Pratt
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Brian J Morris
- Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK,Brian J Morris, Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Joseph Black Building, Glasgow, G12 8QQ, UK.
| |
Collapse
|
|
7
|
Barbosa-Méndez S, Pérez-Sánchez G, Becerril-Villanueva E, Salazar-Juárez A. Melatonin decreases cocaine-induced locomotor sensitization and cocaine-conditioned place preference in rats. J Psychiatr Res 2021; 132:97-110. [PMID: 33080430 DOI: 10.1016/j.jpsychires.2020.09.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 09/11/2020] [Accepted: 09/25/2020] [Indexed: 12/12/2022]
Abstract
Melatonin is a hormone that produces behavioral, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors. Melatonin receptors participate in the modulation of the reinforcing effects of cocaine. Some studies report that dosing of melatonin decreases cocaine-induced locomotor activity and cocaine self-administration and that luzindole, an MT1, and MT2 melatonin receptor antagonist, blocks the melatonin-dependent decrease in cocaine-induced locomotor activity. The objective of this study was to evaluate the effect of acute or chronic dosing of melatonin on the induction and expression of cocaine-induced locomotor sensitization and cocaine-CPP in rats. Male Wistar rats received cocaine during the induction and expression of locomotor sensitization. Melatonin was administered 30 min before cocaine. After each treatment, locomotor activity was recorded for 30 min. Additionally, dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFc), and the ventral tegmental area (VTA) by HPLC in animals treated with melatonin and cocaine. Melatonin decreased cocaine-induced locomotor sensitization and intracellular dopamine levels, as well as cocaine-CPP. Luzindole blocked the melatonin-induced decrease in the expression of locomotor sensitization in rats. These data suggest that melatonin may be a useful therapeutic agent to reduce cocaine abuse; additionally, they suggest that MT1 and MT2 receptors could be therapeutic targets, useful for the treatment of drug abuse disorder.
Collapse
Affiliation(s)
- Susana Barbosa-Méndez
- Subdirección de Investigaciones Clínicas, Laboratorio de Neurofarmacología Conductual, Microcirugía y Terapéutica Experimental, Ciudad de México, 14370, Mexico
| | - Gilberto Pérez-Sánchez
- Dirección de Neurociencias, Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría, Ciudad de México, 14370, Mexico
| | - Enrique Becerril-Villanueva
- Dirección de Neurociencias, Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría, Ciudad de México, 14370, Mexico
| | - Alberto Salazar-Juárez
- Subdirección de Investigaciones Clínicas, Laboratorio de Neurofarmacología Conductual, Microcirugía y Terapéutica Experimental, Ciudad de México, 14370, Mexico.
| |
Collapse
|
|
8
|
Wiechmann AF, Martin TA, Horb ME. CRISPR/Cas9 mediated mutation of the mtnr1a melatonin receptor gene causes rod photoreceptor degeneration in developing Xenopus tropicalis. Sci Rep 2020; 10:13757. [PMID: 32792587 PMCID: PMC7426423 DOI: 10.1038/s41598-020-70735-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 08/03/2020] [Indexed: 11/21/2022] Open
Abstract
Nighttime surges in melatonin levels activate melatonin receptors, which synchronize cellular activities with the natural light/dark cycle. Melatonin receptors are expressed in several cell types in the retina, including the photon-sensitive rods and cones. Previous studies suggest that long-term photoreceptor survival and retinal health is in part reliant on melatonin orchestration of circadian homeostatic activities. This scenario would accordingly envisage that disruption of melatonin receptor signaling is detrimental to photoreceptor health. Using in vivo CRISPR/Cas9 genomic editing, we discovered that a small deletion mutation of the Mel1a melatonin receptor (mtnr1a) gene causes a loss of rod photoreceptors in retinas of developing Xenopus tropicalis heterozygous, but not homozygous mutant tadpoles. Cones were relatively spared from degeneration, and the rod loss phenotype was not obvious after metamorphosis. Localization of Mel1a receptor protein appeared to be about the same in wild type and mutant retinas, suggesting that the mutant protein is expressed at some level in mutant retinal cells. The severe impact on early rod photoreceptor viability may signify a previously underestimated critical role in circadian influences on long-term retinal health and preservation of sight. These data offer evidence that disturbance of homeostatic, circadian signaling, conveyed through a mutated melatonin receptor, is incompatible with rod photoreceptor survival.
Collapse
Affiliation(s)
- Allan F Wiechmann
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
| | - Teryn A Martin
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Marko E Horb
- Marine Biological laboratory, Woods Hole, MA, USA
| |
Collapse
|
|
9
|
Mootz JRK, Miner NB, Phillips TJ. Differential genetic risk for methamphetamine intake confers differential sensitivity to the temperature-altering effects of other addictive drugs. GENES, BRAIN, AND BEHAVIOR 2020; 19:e12640. [PMID: 31925906 PMCID: PMC7286770 DOI: 10.1111/gbb.12640] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/07/2020] [Accepted: 01/07/2020] [Indexed: 01/03/2023]
Abstract
Mice selectively bred for high methamphetamine (MA) drinking (MAHDR), compared with mice bred for low MA drinking (MALDR), exhibit greater sensitivity to MA reward and insensitivity to aversive and hypothermic effects of MA. Previous work identified the trace amine-associated receptor 1 gene (Taar1) as a quantitative trait gene for MA intake that also impacts thermal response to MA. All MAHDR mice are homozygous for the mutant Taar1 m1J allele, whereas all MALDR mice possess at least one copy of the reference Taar1 + allele. To determine if their differential sensitivity to MA-induced hypothermia extends to drugs of similar and different classes, we examined sensitivity to the hypothermic effect of the stimulant cocaine, the amphetamine-like substance 3,4-methylenedioxymethamphetamine (MDMA), and the opioid morphine in these lines. The lines did not differ in thermal response to cocaine, only MALDR mice exhibited a hypothermic response to MDMA, and MAHDR mice were more sensitive to the hypothermic effect of morphine than MALDR mice. We speculated that the μ-opioid receptor gene (Oprm1) impacts morphine response, and genotyped the mice tested for morphine-induced hypothermia. We report genetic linkage between Taar1 and Oprm1; MAHDR mice more often inherit the Oprm1 D2 allele and MALDR mice more often inherit the Oprm1 B6 allele. Data from a family of recombinant inbred mouse strains support the influence of Oprm1 genotype, but not Taar1 genotype, on thermal response to morphine. These results nominate Oprm1 as a genetic risk factor for morphine-induced hypothermia, and provide additional evidence for a connection between drug preference and drug thermal response.
Collapse
Affiliation(s)
- John R K Mootz
- Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, Oregon
| | - Nicholas B Miner
- Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, Oregon
| | - Tamara J Phillips
- Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, Oregon
- Division of Research, Veterans Affairs Portland Health Care System, Portland, Oregon
| |
Collapse
|
|
10
|
Haddar M, Uno K, Azuma K, Muramatsu S, Nitta A. Inhibitory effects of Shati/Nat8l overexpression in the medial prefrontal cortex on methamphetamine-induced conditioned place preference in mice. Addict Biol 2020; 25:e12749. [PMID: 30950164 PMCID: PMC7187255 DOI: 10.1111/adb.12749] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 02/24/2019] [Accepted: 02/28/2019] [Indexed: 11/29/2022]
Abstract
Shati/Nat8l is a novel N-acetyltransferase identified in the brain of mice treated with methamphetamine (METH). Shati/Nat8l mRNA is expressed in various brain areas, including the prefrontal cortex (PFC), where the expression level is higher than that in other brain regions. Shati/Nat8l overexpression in the nucleus accumbens (NAc) attenuates the pharmacological response to METH via mGluR3. Meanwhile, dopamine (DA) and glutamate dysregulations have been reported in the medial prefrontal cortex (mPFC) and NAc after METH self-administration and during reinstatement. However, the mechanism, the reward system, and function of Shati/Nat8l in the mPFC is unclear. Here, we injected an adeno-associated virus (AAV) vector containing Shati/Nat8l into the mPFC of mice, to overexpress Shati/Nat8l in the mPFC (mPFC-Shati/Nat8l). Interestingly, the METH-induced conditioned place preference (CPP) was attenuated in the mPFC-Shati/Nat8l mice, but locomotor activity was not. Additionally, immunohistochemical results from mice that were injected with AAV-GFP showed fluorescence in the mPFC and other brain regions, mainly the NAc, indicating an mPFC-NAc top-down connection. Finally, in vivo microdialysis experiments revealed that Shati/Nat8l overexpression in the mPFC reduced extracellular DA levels and suppressed the METH-induced DA increase in the NAc. Moreover, decreased extracellular glutamate levels were observed in the NAc. These results indicate that Shati/Nat8l overexpression in the mPFC attenuates METH-induced CPP by decreasing extracellular DA in the NAc. In contrast, Shati/Nat8l-mPFC overexpression did not alter METH-induced hyperlocomotion. This study demonstrates that Shati/Nat8l in the mPFC attenuates METH reward-seeking behaviour but not the psychomotor activity of METH.
Collapse
Affiliation(s)
- Meriem Haddar
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical SciencesUniversity of Toyama Toyama Japan
| | - Kyosuke Uno
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical SciencesUniversity of Toyama Toyama Japan
| | - Katsunori Azuma
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical SciencesUniversity of Toyama Toyama Japan
| | - Shin‐ichi Muramatsu
- Division of Neurology, Department of MedicineJichi Medical University Shimotsuke Japan
- Center for Gene and Cell Therapy, The Institute of Medical ScienceThe University of Tokyo Tokyo Japan
| | - Atsumi Nitta
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical SciencesUniversity of Toyama Toyama Japan
| |
Collapse
|
|
11
|
Melatonin MT1 receptor as a novel target in neuropsychopharmacology: MT1 ligands, pathophysiological and therapeutic implications, and perspectives. Pharmacol Res 2019; 144:343-356. [DOI: 10.1016/j.phrs.2019.04.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 03/06/2019] [Accepted: 04/11/2019] [Indexed: 12/15/2022]
|
|
12
|
Onaolapo OJ, Onaolapo AY. Melatonin in drug addiction and addiction management: Exploring an evolving multidimensional relationship. World J Psychiatry 2018; 8:64-74. [PMID: 29988891 PMCID: PMC6033744 DOI: 10.5498/wjp.v8.i2.64] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 05/06/2018] [Accepted: 05/10/2018] [Indexed: 02/05/2023] Open
Abstract
Melatonin is a pleiotropic signalling molecule that regulates several physiological functions, and synchronises biological rhythms. Recent evidences are beginning to reveal that a dysregulation of endogenous melatonin rhythm or action may play a larger role in the aetiology and behavioural expression of drug addiction, than was previously considered. Also, the findings from a number of animal studies suggest that exogenous melatonin supplementation and therapeutic manipulation of melatonin/melatonin receptor interactions may be beneficial in the management of behavioural manifestations of drug addiction. However, repeated exogenous melatonin administration may cause a disruption of its endogenous rhythm and be associated with potential drawbacks that might limit its usefulness. In this review, we examine the roles of melatonin and its receptors in addictive behaviours; discussing how our understanding of melatonin’s modulatory effects on the brain rewards system and crucial neurotransmitters such as dopamine has evolved over the years. Possible indications(s) for melatonergic agents in addiction management, and how manipulations of the endogenous melatonin system may be of benefit are also discussed. Finally, the potential impediments to application of melatonin in the management of addictive behaviours are considered.
Collapse
Affiliation(s)
- Olakunle J Onaolapo
- Behavioural Neuroscience/Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Ladoke Akintola University of Technology, Osogbo 230263, Osun State, Nigeria
| | - Adejoke Y Onaolapo
- Behavioural Neuroscience/Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomosho 210211, Oyo State, Nigeria
| |
Collapse
|
|
13
|
Clough SJ, Hudson RL, Dubocovich ML. Food-induced reinforcement is abrogated by the genetic deletion of the MT 1 or MT 2 melatonin receptor in C3H/HeN mice. Behav Brain Res 2018; 343:28-35. [PMID: 29374562 PMCID: PMC5842708 DOI: 10.1016/j.bbr.2018.01.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 12/17/2017] [Accepted: 01/22/2018] [Indexed: 01/08/2023]
Abstract
Palatable food is known for its ability to enhance reinforcing responses. Studies have suggested a circadian variation in both drug and natural reinforcement, with each following its own time course. The goal of this study was to determine the role of the MT1 and MT2 melatonin receptors in palatable snack food-induced reinforcement, as measured by the conditioned place preference (CPP) paradigm during the light and dark phases. C3H/HeN wild-type mice were trained for snack food-induced CPP at either ZT 6 - 8 (ZT: Zeitgeber time; ZT 0 = lights on), when endogenous melatonin levels are low, or ZT 19 - 21, when melatonin levels are high. These time points also correspond to the high and low points for expression of the circadian gene Period1, respectively. The amount of snack food (chow, Cheetos®, Froot Loops® and Oreos®) consumed was of similar magnitude at both times, however only C3H/HeN mice conditioned to snack food at ZT 6 - 8 developed a place preference. C3H/HeN mice with a genetic deletion of either the MT1 (MT1KO) or MT2 (MT2KO) receptor tested at ZT 6 - 8 did not develop a place preference for snack food. Although the MT2KO mice showed a similar amount of snack food consumed when compared to wild-type mice, the MT1KO mice consumed significantly less than either genotype. We conclude that in our mouse model snack food-induced CPP is dependent on time of day and the presence of the MT1 or MT2 receptors, suggesting a role for melatonin and its receptors in snack food-induced reinforcement.
Collapse
MESH Headings
- Animals
- Conditioning, Psychological/physiology
- Feeding Behavior/physiology
- Feeding Behavior/psychology
- Food
- Male
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Mice, Knockout
- Photoperiod
- Receptor, Melatonin, MT1/deficiency
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT2/deficiency
- Receptor, Melatonin, MT2/genetics
- Reinforcement, Psychology
- Spatial Behavior/physiology
Collapse
Affiliation(s)
- Shannon J Clough
- Department of Pharmacology & Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, United States
| | - Randall L Hudson
- Department of Physiology & Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, United States
| | - Margarita L Dubocovich
- Department of Pharmacology & Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, United States.
| |
Collapse
|
|
14
|
Wiesner CD, Davoli V, Schürger D, Prehn-Kristensen A, Baving L. Melatonin Secretion during a Short Nap Fosters Subsequent Feedback Learning. Front Hum Neurosci 2018; 11:648. [PMID: 29375345 PMCID: PMC5767728 DOI: 10.3389/fnhum.2017.00648] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 12/19/2017] [Indexed: 01/11/2023] Open
Abstract
Sleep helps to protect and renew hippocampus-dependent declarative learning. Less is known about forms of learning that mainly engage the dopaminergic reward system. Animal studies showed that exogenous melatonin modulates the responses of the dopaminergic reward system and acts as a neuroprotectant promoting memory. In humans, melatonin is mainly secreted in darkness during evening hours supporting sleep. In this study, we investigate the effects of a short period of daytime sleep (nap) and endogenous melatonin on reward learning. Twenty-seven healthy, adult students took part in an experiment, either taking a 90-min afternoon nap or watching videos (within-subject design). Before and after the sleep vs. wake interval, saliva melatonin levels and reward learning were measured, and in the nap condition, a polysomnogram was obtained. Reward learning was assessed using a two-alternative probabilistic reinforcement-learning task. Sleep itself and subjective arousal or valence had no significant effects on reward learning. However, this study showed for the first time that an afternoon nap can elicit a small but significant melatonin response in about 41% of the participants and that the magnitude of the melatonin response predicts subsequent reward learning. Only in melatonin responders did a short nap improve reward learning. The difference between melatonin-responders and non-responders occurred very early during learning indicating that melatonin might have improved working memory rather than reward learning. Future studies should use paradigms differentiating working memory and reward learning to clarify which aspect of human feedback learning might profit from melatonin.
Collapse
Affiliation(s)
- Christian D. Wiesner
- Department of Clinical Psychology and Psychotherapy, Institute of Psychology, Christian-Albrechts-University zu Kiel, Kiel, Germany
| | - Valentia Davoli
- Department of Child and Adolescent Psychiatry and Psychotherapy, School of Medicine, Christian-Albrechts-University zu Kiel, Kiel, Germany
| | - David Schürger
- Department of Child and Adolescent Psychiatry and Psychotherapy, School of Medicine, Christian-Albrechts-University zu Kiel, Kiel, Germany
| | - Alexander Prehn-Kristensen
- Department of Child and Adolescent Psychiatry and Psychotherapy, School of Medicine, Christian-Albrechts-University zu Kiel, Kiel, Germany
| | - Lioba Baving
- Department of Child and Adolescent Psychiatry and Psychotherapy, School of Medicine, Christian-Albrechts-University zu Kiel, Kiel, Germany
| |
Collapse
|
|
15
|
Medeiros de Mesquita LS, Garcia RCT, Amaral FG, Peres R, Wood SM, Lucena RDL, Frare EO, Abrahão MV, Marcourakis T, Cipolla-Neto J, Afeche SC. The muscarinic effect of anhydroecgonine methyl ester, a crack cocaine pyrolysis product, impairs melatonin synthesis in the rat pineal gland. Toxicol Res (Camb) 2017; 6:420-431. [PMID: 30090510 PMCID: PMC6060695 DOI: 10.1039/c7tx00009j] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 03/27/2017] [Indexed: 11/21/2022] Open
Abstract
Anhydroecgonine methyl ester (AEME), also called methylecgonidine, is a pyrolysis product of crack cocaine that is neurotoxic and potentiates cocaine-induced sensitization. The sensitization induced by drugs of abuse can be influenced by melatonin, a neuroprotective pineal hormone. In the same way, drugs of abuse like alcohol and methamphetamine can modify melatonin synthesis. The aim of the present work was to investigate the AEME effects on melatonin synthesis in the rat pineal gland. Neurotransmitter systems involved in its effects, antioxidant enzyme activities and the melatonin protective role in AEME-induced toxicity were also evaluated. The animals were injected with AEME i.p. (1.12 mg per kg of body weight per day) or vehicle for 10 consecutive days and the nocturnal pineal melatonin synthesis profile and SOD, GPx and GR activities in the cerebral cortex and hippocampus were assessed. Cultured pineal glands were incubated with AEME for 30 min or 48 h before norepinephrine stimulation and melatonin synthesis, arylalkylamine N-acetyltransferase activity, cAMP and [Ca2+]i were determined. The involvement of cholinergic and glutamatergic systems was analyzed using different antagonists. The protective role of melatonin in AEME toxicity on hippocampal neurons was evaluated by a viability assay. AEME impaired melatonin synthesis both in vivo and in vitro and this effect seems to be mediated by muscarinic receptors and [Ca2+]i elevation. AEME reduced neuronal viability and melatonin was able to protected hippocampal neurons against AEME toxicity. The melatonin synthesis impairment observed could lead to the worsening of the direct AEME neurotoxicity and to the exacerbation of the crack cocaine addiction and sensitization.
Collapse
Affiliation(s)
- Lívia Silva Medeiros de Mesquita
- Laboratory of Pharmacology , Butantan Institute , 05503-000 , São Paulo , SP , Brazil . ; ; ; ; ; ; Tel: +55 11 26279741
- Department of Physiology and Biophysics , Institute of Biomedical Sciences , University of São Paulo , 05508-900 , São Paulo , SP , Brazil . ; ;
| | - Raphael Caio Tamborelli Garcia
- Department of Clinical and Toxicological Analysis , School of Pharmaceutical Sciences , University of São Paulo , 05508-900 , São Paulo , SP , Brazil . ; ;
- Institute of Environmental , Chemical and Pharmaceutical Sciences , Federal University of São Paulo , 09972-270 , São Paulo , SP , Brazil
| | - Fernanda Gaspar Amaral
- Department of Physiology and Biophysics , Institute of Biomedical Sciences , University of São Paulo , 05508-900 , São Paulo , SP , Brazil . ; ;
- Department of Physiology , Federal University of São Paulo , 04023-901 , São Paulo , SP , Brazil
| | - Rafael Peres
- Department of Physiology and Biophysics , Institute of Biomedical Sciences , University of São Paulo , 05508-900 , São Paulo , SP , Brazil . ; ;
- University of Hawaii Cancer Center , Clinical & Translational Research Program , 96813 , Honolulu , HI , USA
| | - Simone Miller Wood
- Department of Clinical and Toxicological Analysis , School of Pharmaceutical Sciences , University of São Paulo , 05508-900 , São Paulo , SP , Brazil . ; ;
| | - RodrigoVincenzo de Luca Lucena
- Laboratory of Pharmacology , Butantan Institute , 05503-000 , São Paulo , SP , Brazil . ; ; ; ; ; ; Tel: +55 11 26279741
| | - Eduardo Osório Frare
- Laboratory of Pharmacology , Butantan Institute , 05503-000 , São Paulo , SP , Brazil . ; ; ; ; ; ; Tel: +55 11 26279741
| | - Mariana Vieira Abrahão
- Laboratory of Pharmacology , Butantan Institute , 05503-000 , São Paulo , SP , Brazil . ; ; ; ; ; ; Tel: +55 11 26279741
| | - Tania Marcourakis
- Department of Clinical and Toxicological Analysis , School of Pharmaceutical Sciences , University of São Paulo , 05508-900 , São Paulo , SP , Brazil . ; ;
| | - José Cipolla-Neto
- Department of Physiology and Biophysics , Institute of Biomedical Sciences , University of São Paulo , 05508-900 , São Paulo , SP , Brazil . ; ;
| | - Solange Castro Afeche
- Laboratory of Pharmacology , Butantan Institute , 05503-000 , São Paulo , SP , Brazil . ; ; ; ; ; ; Tel: +55 11 26279741
| |
Collapse
|
|
16
|
Rawashdeh O, Clough SJ, Hudson RL, Dubocovich ML. Learned motivation drives circadian physiology in the absence of the master circadian clock. FASEB J 2016; 31:388-399. [PMID: 27733449 DOI: 10.1096/fj.201600926r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 09/28/2016] [Indexed: 01/23/2023]
Abstract
The suprachiasmatic nucleus (SCN)-often referred to as the master circadian clock-is essential in generating physiologic rhythms and orchestrating synchrony among circadian clocks. This study tested the hypothesis that periodic motivation induced by rhythmically pairing 2 reinforcing stimuli [methamphetamine (Meth) and running wheel (RW)] restores autonomous circadian activity in arrhythmic SCN-lesioned (SCNX) C3H/HeN mice. Sham-surgery and SCNX mice were treated with either Meth (1.2 mg/kg, i.p.) or vehicle in association, dissociation, or absence of an RW. Only the association of Meth treatment and restricted RW access successfully reestablished entrained circadian rhythms in mice with SCNX. RW-likely acting as a link between the circadian and reward systems-promotes circadian entrainment of activity. We conclude that a conditioned drug response is a powerful tool to entrain, drive, and restore circadian physiology. Furthermore, an RW should be recognized as a potent input signal in addition to the conventional use as an output signal.-Rawashdeh, O., Clough, S. J., Hudson, R. L., Dubocovich, M. L. Learned motivation drives circadian physiology in the absence of the master circadian clock.
Collapse
Affiliation(s)
- Oliver Rawashdeh
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Shannon J Clough
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Randall L Hudson
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
| | - Margarita L Dubocovich
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA;
| |
Collapse
|
|
17
|
Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol 2016; 173:2702-25. [PMID: 27314810 DOI: 10.1111/bph.13536] [Citation(s) in RCA: 304] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 05/15/2016] [Accepted: 05/19/2016] [Indexed: 02/06/2023] Open
Abstract
Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist - MT1 and MT2 - encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.
Collapse
Affiliation(s)
- Ralf Jockers
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,University Paris Descartes, Paris, France
| | | | - Margarita L Dubocovich
- Department Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Science, University at Buffalo (SUNY), Buffalo, USA
| | - Regina P Markus
- Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | | | - Gianluca Tosini
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Erika Cecon
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,University Paris Descartes, Paris, France
| | - Darius P Zlotos
- Department of Pharmaceutical Chemistry, The German University in Cairo, New Cairo City, Cairo, Egypt
| |
Collapse
|
|
18
|
Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol 2015; 56:361-83. [PMID: 26514204 PMCID: PMC5091650 DOI: 10.1146/annurev-pharmtox-010814-124742] [Citation(s) in RCA: 423] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein-coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents.
Collapse
Affiliation(s)
- Jiabei Liu
- Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214; , , , , ,
| | - Shannon J Clough
- Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214; , , , , ,
| | - Anthony J Hutchinson
- Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214; , , , , ,
| | - Ekue B Adamah-Biassi
- Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214; , , , , ,
| | - Marina Popovska-Gorevski
- Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214; , , , , ,
| | - Margarita L Dubocovich
- Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214; , , , , ,
| |
Collapse
|
|
19
|
Phillips TJ, Shabani S. An animal model of differential genetic risk for methamphetamine intake. Front Neurosci 2015; 9:327. [PMID: 26441502 PMCID: PMC4585292 DOI: 10.3389/fnins.2015.00327] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 08/31/2015] [Indexed: 11/13/2022] Open
Abstract
The question of whether genetic factors contribute to risk for methamphetamine (MA) use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine-associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the development of a binge model of MA intake, examining the effect of withdrawal from chronic MA on MA intake, and studying potential Taar1 gene × gene and gene × environment interactions. These and other studies are intended to improve our genetic model with regard to its translational value to human addiction.
Collapse
Affiliation(s)
- Tamara J. Phillips
- VA Portland Health Care SystemPortland, OR, USA
- Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science UniversityPortland, OR, USA
| | | |
Collapse
|