DOCSLIB.ORG

The Role of Selective Serotonin Reuptake Inhibitors in Reducing Alcohol Consumption

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Selective Serotonin Reuptake Inhibitors in Reducing Alcohol Consumption Naranjo and Knoke The Role of Selective Serotonin Reuptake Inhibitors in Reducing Alcohol Consumption Claudio A. Naranjo, M.D., and Della M. Knoke, M.A. © CopyrightPreclinical and clinical 2001 studies Physicians demonstrated an inverse Postgraduate relationship between serotonergic Press, activity Inc. and alcohol consumption. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, and fluvoxamine have subsequently been examined for their ability to reduce alcohol consumption in alcoholic subjects. Interindividual variability in response to SSRIs is large, with reductions in alcohol consumption ranging from 10% to more than 70%. Several factors, including gender, alcoholic sub- type, and extent of drinking, appear to affect the treatment efficacy of the SSRIs. A significant chal- lenge for researchers is to identify the subject variables that predict treatment response, providing a basis for guiding alcohol-dependent individuals to the treatment that is most likely to be effective for them. This article reviews the available clinical studies, discusses possible mechanisms of action for the SSRIs, and describes a model for predicting treatment responses in alcoholic subjects. (J Clin Psychiatry 2001;62[suppl 20]:18–25) One personal copy may be printed he development of substance use disorders results Serotonin plays an important role in several aspects of ad- T from the interaction of drugs of abuse with multiple diction, including reward, craving, and relapse. neurochemical substrates within a social and cultural con- text. Although the present article focuses on the role of se- STUDIES IN ANIMALS rotonin, various neurotransmitter and receptor systems have been associated with drug reward and the patho- Several inbred strains of alcohol-preferring animals physiology of substance use disorders.1 Substantial evi- have been selected from heterogeneous populations and dence supports the role of direct or indirect stimulation of examined as animal models of genetic predisposition for dopaminergic neurotransmission as a fundamental prop- alcohol preference. Reduced levels of serotonin (5-HT) erty of drugs of abuse, including cocaine, opioids, nico- and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) tine, and ethanol in both animals and humans.2–4 In addi- have been found in alcohol-preferring mice and rats (e.g., tion, drug reward is also mediated by the opioid system AA rats and C57BL6J mice) before ethanol exposure and (including the amygdala, locus ceruleus, and periaque- after washout, suggesting reduced serotonin synthesis (for ductal gray area) and the γ-aminobutyric acid system in- reviews, see LeMarquand et al.5 and Li and McBride6). corporating the cortex, cerebellum, hippocampus, and These results suggest an inverse relationship between se- nucleus accumbens. Other neural systems such as acetyl- rotonin concentrations and alcohol preference. choline and various other neuropeptides may also have In the 1980s, several selective serotonin reuptake in- roles in the pathophysiology of substance use disorders. hibitors (SSRIs) became available, mostly as novel anti- depressants in various stages of development. SSRIs block the serotonin uptake pump, enhancing serotonin neuro- transmission. Therefore, these agents provided an oppor- tunity to examine the impact on alcohol consumption of From the Departments of Pharmacology, Psychiatry, increasing serotonergic neurotransmission (for a review, and Medicine, University of Toronto, Psychopharmacology see Naranjo and Bremner7). Preference paradigms were Research Program, Sunnybrook and Women’s College Health Sciences Centre, Sunnybrook Campus, Toronto, Ontario, employed to provide rats the choice of a nonalcoholic Canada. solution or an alcoholic solution. Precision in recording Presented at the closed roundtable symposium “Pharmacological Treatment of Alcohol Abuse and Addiction,” improved with the development of a “drinkometer” (an which was held on February 28, 2000, in Philadelphia, Pa., electronic device for measuring alcohol intake) with a and supported by an unrestricted educational grant from pressure transducer, developed with our biomedical engi- Forest Laboratories, Inc. Reprint requests to: Claudio A. Naranjo, M.D., University of neering colleagues. This drinkometer was connected to a Toronto, Sunnybrook and Women’s College Health Sciences Hewlett-Packard computer, and the data were transcribed Centre, Sunnybrook Campus, Psychopharmacology Research Program, Room F327, 2075 Bayview Ave., Toronto, Ontario, as they were acquired. Research using preference and Canada M4N 3M5. other paradigms consistently reported that a variety of 18 J Clin Psychiatry 2001;62 (suppl 20) SSRIs in Reducing Alcohol Consumption Table 1. Fluoxetine and Alcoholism: Placebo-Controlled Studies provides a direct measurement of Treatment drug effect. Study Type of Drinker (N) Dose Duration Parameters Outcome or dependent mea- Naranjo et al, 199019 Mild to moderate (29) 40 mg/d 4 weeks ∆ drinks/d sures vary from study to study de- ∆ abstinence pending on the treatment goals 60 mg/d 4 weeks ∆ drinks/d ∆ abstinence set. For example, in Canada, mod- Gorelick and Paredes, 199220 Dependent (20) Up to 80 mg/d 4 weeks ∆ drinks/d eration of alcohol intake is an ac- Naranjo et al, 199421 Mild to moderate (16) 60 mg/d 2 weeks ∆ drinks/d ceptable goal in human studies of ∆ abstinence Kranzler et al, 199522 Dependent (101) Up to 60 mg/d 12 weeks ∆ drinks/d mildly to moderately dependent individuals. Abstinence is consid- © Copyright 2001 Physicians Postgraduateered thePress, preferred Inc. goal for indi- SSRIs reduced alcohol consumption by 50% to 70%, viduals who are highly dependent. In the United States, depending on the SSRI dose administered8 (for a review, however, abstinence is the preferred goal for all levels of see LeMarquand et al.5) dependence. Although abstinence is explicitly advised Results of animal studies provided a basis for early and preferred in many studies, drinking during treatment clinical pharmacologic tests. Some difficulties were ap- is often recorded to monitor “slips” (any return to drink- parent in extrapolating from rat to human studies. For ex- ing) and relapses (5 drinks for men or 4 for women in 1 ample, it was difficult to extrapolate from rat studies the sitting).10 SSRI dose required to reduce alcohol consumption in hu- mans. In clinical practice, the desired doses are within the Serotonin Reuptake Inhibitors therapeutic range for antidepressant effect. In addition, and Alcohol Consumption the standards for assessing efficacy Oneoften personaldiffer in animal copy may Correlationalbe printed studies of alcohol-dependent individuals and human studies. Efficacy in animal studies is depen- suggest that brain serotonergic activity is inversely dent on the drug’s ability to reduce alcohol consumption. related to ethanol consumption. Abstinent alcoholics However, in the United States, human studies often seek have been shown to have reduced cerebrospinal fluid to evaluate the drug’s ability to maintain a state of absti- (CSF) 5-HIAA levels,11,12 low platelet 5-HT content,13 nence. Thus, although animal models of alcoholism pro- and low tryptophan availability in plasma,14 suggesting vide a mechanism for screening new drugs, the clinical decreased central serotonergic function. In addition, value of a new medication is ultimately dependent on the although results are mixed, blunted neuroendocrine re- results of human studies. sponses have been documented in detoxified alcoholics administered m-chlorophenylpiperazine,15 MK212,16 and STUDIES IN HUMANS fenfluramine,17,18 suggesting reduced responsivity of the serotonergic system. Protocols assessing the effect of medication on alcohol An inverse relationship between serotonergic activity consumption tend to be similar. At intake, psychosocial and alcohol consumption is also partially supported by tests are administered to assess degree of alcohol depen- studies examining the impact of serotonergic agonists on dence (e.g., the Alcohol Dependence Scale), psychologi- ethanol intake. Although administration of 5-HIAA pre- cal/psychiatric status, and level of function (DSM-IV). cursors had no effect on alcohol intake, several selective In addition, a brief medical assessment, laboratory tests, serotonin reuptake inhibitors have been employed with and a urine screen for drugs of abuse are included to as- some success. Tables 1 through 3 summarize studies ex- sess medical eligibility for participation. Once included in amining the effect of SSRIs on alcohol consumption and the study, subjects monitor on a daily basis alcohol intake, craving. tobacco use, and use of the study medication. Compliance The first SSRIs available for testing were zimelidine can be assessed by adding riboflavin to the study medica- and viqualine. Although research on these agents sug- tion and then measuring the concentration of riboflavin in gested that they reliably reduced alcohol consumption, the urine. During the baseline phase, riboflavin concen- the appearance of significant adverse effects led to a tration in urine is relatively low, followed by a 7- to 12- withdrawal of these agents from the market. Fluoxetine, fold increase when subjects take the medication. Studies fluvoxamine, citalopram, paroxetine, and sertraline were that include a washout period show reductions in ribo- all subsequently introduced. Using the IC50 ratio to mea- flavin during this period, with increases once treatment sure the in vitro competitive inhibition
Load more

Recommended publications
  • Serotonin's Role in Alcohol's Effects on the Brain
    NEUROTRANSMITTER REVIEW IMPERATO, A., AND DI CHIARA, G. Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. Journal SEROTONIN’S ROLE IN ALCOHOL’S of Pharmacology and Experimental Therapeutics 239:219–228, 1986. EFFECTS ON THE BRAIN KITAI, S.T., AND SURMEIER, D.J. Cholinergic and dopaminergic modula- tion of potassium conductances in neostriatal neurons. Advances in David M. Lovinger, Ph.D. Neurology 60:40–52, 1993. LE MOINE, C.; NORMAND, E.; GUITTENY, A.F.; FOUQUE, B.; TEOULE, R.; AND BLOCH, B. Dopamine receptor gene expression by enkephalin Serotonin is an important brain chemical that acts as a neurons in rat forebrain. Proceedings of the National Academy of Sciences neurotransmitter to communicate information among USA 87:230–234, 1990. nerve cells. Serotonin’s actions have been linked to al- LE MOINE, C.; NORMAND, E.; AND BLOCH, B. Phenotypical character- cohol’s effects on the brain and to alcohol abuse. ization of the rat striatal neurons expressing the D1 dopamine receptor Alcoholics and experimental animals that consume gene. Proceedings of the National Academy of Sciences USA 88: large quantities of alcohol show evidence of differences 4205–4209, 1991. in brain serotonin levels compared with nonalcoholics. LYNESS, W.H., AND SMITH F.L. Influence of dopaminergic and sero- Both short- and long-term alcohol exposure also affect tonergic neurons on intravenous ethanol self-administration in the rat. the serotonin receptors that convert the chemical sig- Pharmacology and Biochemistry of Behavior 42:187–192, 1992. nal produced by serotonin into functional changes in the signal-receiving cell.
    [Show full text]
  • The Serotonergic System in Migraine Andrea Rigamonti Domenico D’Amico Licia Grazzi Susanna Usai Gennaro Bussone
    J Headache Pain (2001) 2:S43–S46 © Springer-Verlag 2001 MIGRAINE AND PATHOPHYSIOLOGY Massimo Leone The serotonergic system in migraine Andrea Rigamonti Domenico D’Amico Licia Grazzi Susanna Usai Gennaro Bussone Abstract Serotonin (5-HT) and induce migraine attacks. Moreover serotonin receptors play an impor- different pharmacological preventive tant role in migraine pathophysiolo- therapies (pizotifen, cyproheptadine gy. Changes in platelet 5-HT content and methysergide) are antagonist of are not casually related, but they the same receptor class. On the other may reflect similar changes at a neu- side the activation of 5-HT1B-1D ronal level. Seven different classes receptors (triptans and ergotamines) of serotoninergic receptors are induce a vasocostriction, a block of known, nevertheless only 5-HT2B-2C neurogenic inflammation and pain M. Leone • A. Rigamonti • D. D’Amico and 5HT1B-1D are related to migraine transmission. L. Grazzi • S. Usai • G. Bussone (౧) syndrome. Pharmacological evi- C. Besta National Neurological Institute, Via Celoria 11, I-20133 Milan, Italy dences suggest that migraine is due Key words Serotonin • Migraine • e-mail: [email protected] to an hypersensitivity of 5-HT2B-2C Triptans • m-Chlorophenylpiperazine • Tel.: +39-02-2394264 receptors. m-Chlorophenylpiperazine Pathogenesis Fax: +39-02-70638067 (mCPP), a 5-HT2B-2C agonist, may The 5-HT receptor family is distinguished from all other 5- Introduction 1 HT receptors by the absence of introns in the genes; in addi- tion all are inhibitors of adenylate cyclase [1]. Serotonin (5-HT) and serotonin receptors play an important The 5-HT1A receptor has a high selective affinity for 8- role in migraine pathophysiology.
    [Show full text]
  • THE USE of MIRTAZAPINE AS a HYPNOTIC O Uso Da Mirtazapina Como Hipnótico Francisca Magalhães Scoralicka, Einstein Francisco Camargosa, Otávio Toledo Nóbregaa
    ARTIGO ESPECIAL THE USE OF MIRTAZAPINE AS A HYPNOTIC O uso da mirtazapina como hipnótico Francisca Magalhães Scoralicka, Einstein Francisco Camargosa, Otávio Toledo Nóbregaa Prescription of approved hypnotics for insomnia decreased by more than 50%, whereas of antidepressive agents outstripped that of hypnotics. However, there is little data on their efficacy to treat insomnia, and many of these medications may be associated with known side effects. Antidepressants are associated with various effects on sleep patterns, depending on the intrinsic pharmacological properties of the active agent, such as degree of inhibition of serotonin or noradrenaline reuptake, effects on 5-HT1A and 5-HT2 receptors, action(s) at alpha-adrenoceptors, and/or histamine H1 sites. Mirtazapine is a noradrenergic and specific serotonergic antidepressive agent that acts by antagonizing alpha-2 adrenergic receptors and blocking 5-HT2 and 5-HT3 receptors. It has high affinity for histamine H1 receptors, low affinity for dopaminergic receptors, and lacks anticholinergic activity. In spite of these potential beneficial effects of mirtazapine on sleep, no placebo-controlled randomized clinical trials of ABSTRACT mirtazapine in primary insomniacs have been conducted. Mirtazapine was associated with improvements in sleep on normal sleepers and depressed patients. The most common side effects of mirtazapine, i.e. dry mouth, drowsiness, increased appetite and increased body weight, were mostly mild and transient. Considering its use in elderly people, this paper provides a revision about studies regarding mirtazapine for sleep disorders. KEYWORDS: sleep; antidepressive agents; sleep disorders; treatment� A prescrição de hipnóticos aprovados para insônia diminuiu em mais de 50%, enquanto de antidepressivos ultrapassou a dos primeiros.
    [Show full text]
  • MDMA) Cause Selective Ablation of Serotonergic Axon Terminals in Forebrain: Lmmunocytochemical Evidence for Neurotoxicity
    The Journal of Neuroscience, August 1988, 8(8): 2788-2803 Methylenedioxyamphetamine (MDA) and Methylenedioxymetham- phetamine (MDMA) Cause Selective Ablation of Serotonergic Axon Terminals in Forebrain: lmmunocytochemical Evidence for Neurotoxicity E. O’Hearn,” G. Battaglia, lab E. B. De Souza,’ M. J. Kuhar,’ and M. E. Molliver Departments of Neuroscience, and Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and ‘Neuroscience Branch, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland 21224 The psychotropic amphetamine derivatives 3,4-methylene- The synthetic amphetamine derivatives 3,4-methylenedioxy- dioxyamphetamine (MDA) and 3,4-methylenedioxymetham- amphetamine (MDA) and 3,4-methylenedioxymethamphet- phetamine (MDMA) have been used for recreational and amine (MDMA) are potent mood-altering drugs that have at- therapeutic purposes in man. In rats, these drugs cause large tained public interest (Seymour, 1986) due to their widespread, reductions in brain levels of serotonin (5HT). This study self-administration by young adults (e.g., Klein, 1985). These employs immunocytochemistry to characterize the neuro- drugs have also been proposed for medical use in psychotherapy toxic effects of these compounds upon monoaminergic neu- because they produce augmentation of mood and enhanced in- rons in the rat brain. Two weeks after systemic administra- sight (Naranjo et al., 1967; Yensen et al., 1976; Di Leo, 198 1; tion of MDA or MDMA (20 mg/kg, s.c., twice daily for 4 d), Greer and Tolbert, 1986; Grinspoon and Bakalar, 1986). How- there is profound loss of serotonergic (5HT) axons through- ever, concern has been raised about the safety of these com- out the forebrain; catecholamine axons are completely pounds based on evidence that they may be toxic to brain seroto- spared.
    [Show full text]
  • 5-HT3 Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: the Iceberg Still Lies Beneath the Surface
    1521-0081/71/3/383–412$35.00 https://doi.org/10.1124/pr.118.015487 PHARMACOLOGICAL REVIEWS Pharmacol Rev 71:383–412, July 2019 Copyright © 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: JEFFREY M. WITKIN 5-HT3 Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface Gohar Fakhfouri,1 Reza Rahimian,1 Jonas Dyhrfjeld-Johnsen, Mohammad Reza Zirak, and Jean-Martin Beaulieu Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.) Abstract. ....................................................................................384 I. Introduction. ..............................................................................384 II. 5-HT3 Receptor Structure, Distribution, and Ligands.........................................384 A. 5-HT3 Receptor Agonists .................................................................385 B. 5-HT3 Receptor Antagonists. ............................................................385 Downloaded from 1. 5-HT3 Receptor Competitive Antagonists..............................................385 2. 5-HT3 Receptor
    [Show full text]
  • Alcohol Dependence and Withdrawal Impair Serotonergic Regulation Of
    Research Articles: Cellular/Molecular Alcohol dependence and withdrawal impair serotonergic regulation of GABA transmission in the rat central nucleus of the amygdala https://doi.org/10.1523/JNEUROSCI.0733-20.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.0733-20.2020 Received: 30 March 2020 Revised: 8 July 2020 Accepted: 14 July 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 the authors 1 Alcohol dependence and withdrawal impair serotonergic regulation of GABA 2 transmission in the rat central nucleus of the amygdala 3 Abbreviated title: Alcohol dependence impairs CeA regulation by 5-HT 4 Sophia Khom, Sarah A. Wolfe, Reesha R. Patel, Dean Kirson, David M. Hedges, Florence P. 5 Varodayan, Michal Bajo, and Marisa Roberto$ 6 The Scripps Research Institute, Department of Molecular Medicine, 10550 N. Torrey Pines 7 Road, La Jolla CA 92307 8 $To whom correspondence should be addressed: 9 Dr. Marisa Roberto 10 Department of Molecular Medicine 11 The Scripps Research Institute 12 10550 N. Torrey Pines Road, La Jolla, CA 92037 13 Tel: (858) 784-7262 Fax: (858) 784-7405 14 Email: [email protected] 15 16 Number of pages: 30 17 Number of figures: 7 18 Number of tables: 2 19 Number of words (Abstract): 250 20 Number of words (Introduction): 650 21 Number of words (Discussion): 1500 22 23 The authors declare no conflict of interest.
    [Show full text]
  • The Role of Serotonin in Alcohol's Effects on the Brain
    The Role of Serotonin in Alcohol’s Effects on the Brain David M. Lovinger, Ph.D. Serotonin is an important brain chemical that acts as a neurotransmitter Department of Molecular to communicate information among nerve cells. Serotonin’s actions have Physiology and Biophysics been linked to alcohol’s effects on the brain and to alcohol abuse. Vanderbilt University School of Medicine Alcoholics and experimental animals that consume large quantities of Nashville, TN 37232-0615 alcohol show evidence of differences in brain serotonin levels compared with nonalcoholics. Both short- and long-term alcohol exposures also affect the serotonin receptors that convert the chemical signal produced by serotonin into functional changes in the signal-receiving cell. Drugs that act on these receptors alter alcohol consumption in both humans and animals. Serotonin, along with other neurotransmitters, also may contribute to alcohol’s intoxicating and rewarding effects, and abnormalities in the brain’s serotonin system appear to play an important role in the brain processes underlying alcohol abuse. Neurotransmitters are chemicals This article reviews serotonin’s plays an important role in the control that allow signal transmission, and function in the brain and the conse- of emotions, and the nucleus accum- thus communication, among nerve quences of acute and chronic alcohol bens, a brain area involved in con- cells (i.e., neurons). One neurotrans- consumption on serotonin-mediated trolling the motivation to perform mitter used by many neurons (i.e., serotonergic) signal transmis- certain behaviors, including the throughout the brain is serotonin, sion. In addition, the article summa- abuse of alcohol and other drugs.
    [Show full text]
  • 5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice
    Neuropsychopharmacology (2017) 42, 2163–2177 © 2017 American College of Neuropsychopharmacology. All rights reserved 0893-133X/17 www.neuropsychopharmacology.org 5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice 1 1,2 3,7 4 1 Vladimir M Pogorelov , Ramona M Rodriguiz , Jianjun Cheng , Mei Huang , Claire M Schmerberg , 4 5 3 ,1,2,6 Herbert Y Meltzer , Bryan L Roth , Alan P Kozikowski and William C Wetsel* 1 2 Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; Mouse Behavioral and Neuroendocrine 3 Analysis Core Facility, Duke University Medical Center, Durham, NC, USA; Drug Discovery Program, Department of Medicinal Chemistry and 4 Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, IL, USA; Department of Psychiatry and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 5National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 6 USA; Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC, USA All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or serotonin (5-HT2A) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT receptors may be a promising target for 2C schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities.
    [Show full text]
  • Repeated Exposure to MDMA Triggers Long-Term Plasticity of Noradrenergic and Serotonergic Neurons
    Molecular Psychiatry (2014) 19, 823–833 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons C Lanteri1,2,3, EL Doucet1,2,3, SJ Herna´ndez Vallejo4, G Godeheu1,2,3, A-C Bobadilla1,2,3, L Salomon5, L Lanfumey6 and J-P Tassin1,2,3 3,4-Methylenedioxymethamphetamine (MDMA or ‘ecstasy’) is a psychostimulant drug, widely used recreationally among young people in Europe and North America. Although its neurotoxicity has been extensively described, little is known about its ability to strengthen neural circuits when administered in a manner that reproduces human abuse (i.e. repeated exposure to a low dose). C57BL/6J mice were repeatedly injected with MDMA (10 mg kg À 1, intraperitoneally) and studied after a 4-day or a 1-month withdrawal. We show, using in vivo microdialysis and locomotor activity monitoring, that repeated injections of MDMA induce a long-term sensitization of noradrenergic and serotonergic neurons, which correlates with behavioral sensitization. The development of this phenomenon, which lasts for at least 1 month after withdrawal, requires repeated stimulation of a1B-adrenergic and 5-hydroxytryptamine (5-HT)2A receptors. Moreover, behavioral and neuroendocrine assays indicate that hyper-reactivity of noradrenergic and serotonergic networks is associated with a persistent desensitization of somatodendritic a2A-adrenergic and 5-HT1A autoreceptor function. Finally, molecular analysis including radiolabeling, western blot and quantitative reverse transcription-polymerase chain reaction reveals that mice repeatedly treated with MDMA exhibit normal a2A-adrenergic and 5-HT1A receptor binding, but a long-lasting downregulation of Gai proteins expression in both locus coeruleus and dorsal raphe nucleus.
    [Show full text]
  • Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala
    6842 • The Journal of Neuroscience, September 2, 2020 • 40(36):6842–6853 Cellular/Molecular Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala Sophia Khom, Sarah A. Wolfe, Reesha R. Patel, Dean Kirson, David M. Hedges, Florence P. Varodayan, Michal Bajo, and Marisa Roberto Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307 Excessive serotonin (5-HT) signaling plays a critical role in the etiology of alcohol use disorder. The central nucleus of the amygdala (CeA) is a key player in alcohol-dependence associated behaviors. The CeA receives dense innervation from the dor- sal raphe nucleus, the major source of 5-HT, and expresses 5-HT receptor subtypes (e.g., 5-HT2C and 5-HT1A) critically linked to alcohol use disorder. Notably, the role of 5-HT regulating rat CeA activity in alcohol dependence is poorly investi- gated. Here, we examined neuroadaptations of CeA 5-HT signaling in adult, male Sprague Dawley rats using an established model of alcohol dependence (chronic intermittent alcohol vapor exposure), ex vivo slice electrophysiology and ISH. 5-HT increased frequency of sIPSCs without affecting postsynaptic measures, suggesting increased CeA GABA release in naive rats. In dependent rats, this 5-HT-induced increase of GABA release was attenuated, suggesting blunted CeA 5-HT sensitivity, which partially recovered in protracted withdrawal (2 weeks). 5-HT increased vesicular GABA release in naive and dependent rats but had split effects (increase and decrease) after protracted withdrawal indicative of neuroadaptations of presynaptic 5- HT receptors. Accordingly, 5-HT abolished spontaneous neuronal firing in naive and dependent rats but had bidirectional effects in withdrawn.
    [Show full text]
  • 5-HT Receptors Review
    Neuronal 5-HT Receptors and SERT Nicholas M. Barnes1 and John F. Neumaier2 1Cellular and Molecular Neuropharmacology Research Group, Section of Neuropharmacology and Neurobiology, Clinical and Experimental Medicine, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT UK and 2Department of Psychiatry, University of Washington, Seattle, WA 98104 USA. Correspondence: [email protected] and [email protected] Nicholas Barnes is Professor of Neuropharmacology at the University of Birmingham Medical School, and focuses on serotonin receptors and the serotonin transporter. John Neumaier is Professor of Psychiatry and Behavioural Sciences and Director of the Division of Neurosciences at the University of Washington. His research concerns the role of serotonin receptors in emotional behavior. Contents Introduction Introduction ........................................................................ 1 5-hydroxytryptamine (5-HT, serotonin) is an ancient biochemical manipulated through evolution to be DRIVING RESEARCH FURTHER The 5-HT1 Receptor Family ............................................... 1 utilized extensively throughout the animal and plant kingdoms. Mammals employ 5-HT as a 5-HT Receptors ............................................................ 2 1A neurotransmitter within the central and peripheral nervous systems, and also as a local hormone in 5-HT Receptors ............................................................ 2 1B numerous other tissues, including the gastrointestinal tract, the cardiovascular
    [Show full text]
  • Antidepressants: Mechanism of Action, Toxicity and Possible Amelioration
    Journal of Applied Biotechnology & Bioengineering Research Article Open Access Antidepressants: mechanism of action, toxicity and possible amelioration Abstract Volume 3 Issue 5 - 2017 Depression being a state of sadness may be defined as a psychoneurotic disorder Khushboo, Sharma B characterised by mental and functional activity, sadness, reduction in activity, Department of Biochemistry, University of Allahabad, India difficulty in thinking, loss of concentration, perturbations in appetite, sleeping, and feelings of dejection, hopelessness and generation of suicidal tendencies. It Correspondence: B Sharma, Department of Biochemistry, is a common and recurrent disorder causing significant morbidity and mortality University of Allahabad, Allahabad 211002, UP, India, worldwide. The antidepressant compounds used against depression are reported to Email [email protected] be used also for treating pain, anxiety syndromes etc. They have been grouped in five different categories such as Received: June 29, 2017 | Published: September 01, 2017 i. Tricyclic antidepressants (TCAs) ii. Selective serotonin-reuptake inhibitors (SSRIs) iii. Monoamine oxidase inhibitors (MAOIs) iv. Serotonin-norepinephrine reuptake inhibitor (SNRI) and v. Non-TCA antidepressants based on their mode of action. Most of the antidepressants have been reported to possess adverse effects on the health of users. The present review article focuses on an updated current of antidepressants, their mechanism of actions, pathophysiology of these compounds, their side effects and
    [Show full text]