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Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys

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Abstract

Rationale

Accumulating evidence shows that the serotonergic system plays a major role in psychostimulant abuse through its interactions with the dopaminergic system. Studies indicate that serotonin 5-HT2C receptors are one of the main classes of receptors involved in mediating the influence of serotonin in drug abuse.

Objective

The aim of the present study was to evaluate the effects of the selective serotonin 5-HT2C receptor agonist WAY163909 on the behavioral neuropharmacology of cocaine and methamphetamine in adult rhesus macaques.

Methods

Cocaine or methamphetamine self-administration and reinstatement were evaluated under second-order and fixed-ratio schedules of reinforcement, respectively. Cocaine- and methamphetamine-induced increases in dopamine were assessed through in vivo microdialysis targeting the nucleus accumbens.

Results

Pretreatment with WAY163909 dose-dependently attenuated cocaine and methamphetamine self-administration and drug-induced reinstatement of extinguished behavior previously maintained by cocaine or methamphetamine delivery. In an additional experiment, WAY163909 induced a dose-dependent attenuation of cocaine- or methamphetamine-induced dopamine overflow in the nucleus accumbens.

Conclusions

Our data indicate that selective 5-HT2C receptor activation decreases drug intake and drug-seeking behavior in nonhuman primate models of psychostimulant abuse through neurochemical mechanisms involved in the modulation of mesolimbic dopamine.

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References

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. Washington, DC.

  • Berro LF, Andersen ML, Tufik S, Howell LL (2017) Effects of GABAA receptor positive allosteric modulators on the behavioral and neurochemical effects of methamphetamine in rhesus monkeys. Neuropharmacology 2017 doi: 10.1016/j.neuropharm.2017.05.010.

  • Bubar MJ, Cunningham KA (2006) Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence. Curr Top Med Chem 6:1971–1985

  • Bubar MJ, Cunningham KA (2008) Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse. Prog Brain res 172:319–346

    Article  CAS  PubMed  Google Scholar 

  • Burbassi S, Cervo L (2008) Stimulation of serotonin2C receptors influences cocaine-seeking behavior in response to drug-associated stimuli in rats. Psychopharmacology 196:15–27

    Article  CAS  PubMed  Google Scholar 

  • Cunningham KA, Fox RG, Anastasio NC, Bubar MJ, Stutz SJ, Moeller FG, Gilbertson SR, Rosenzweig-Lipson S (2011) Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues. Neuropharmacology 61:513–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cunningham KA, Anastasio NC, Fox RG, Stutz SJ, Bubar MJ, Swinford SE et al (2013) Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction. ACS Chem Neurosci 4:110–121

    Article  CAS  PubMed  Google Scholar 

  • Czoty PW, Ginsburg BC, Howell LL (2002) Serotonergic attenuation of the reinforcing and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 300:831–837

    Article  CAS  PubMed  Google Scholar 

  • Dunlop J, Sabb AL, Mazandarani H, Zhang J, Kalgaonker S, Shukhina E et al (2005) WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine 2C receptor-selective agonist with anorectic activity. J Pharmacol Exp Ther 313:862–869

  • Dunlop J, Watts SW, Barrett JE, Coupet J, Harrison B, Mazandarani H, Nawoschik S, Pangalos MN, Ramamoorthy S, Schechter L, Smith D, Stack G, Zhang J, Zhang G, Rosenzweig-Lipson S (2011) Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist. J Pharmacol Exp Ther 337:673–680

    Article  CAS  PubMed  Google Scholar 

  • Epstein DH, Preston KL, Stewart J, Shaham Y (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189:1–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fletcher PJ, Rizos Z, Sinyard J, Tampakeras M, Higgins GA (2008) The 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor yohimbine, and contextual cues. Neuropsychopharmacology 33:1402–1412

    Article  CAS  PubMed  Google Scholar 

  • Grottick AJ, Fletcher PJ, Higgins GA (2000) Studies to investigate the role of 5-HT(2C) receptors on cocaine- and food-maintained behavior. J Pharmacol Exp Ther 295:1183–1191

    CAS  PubMed  Google Scholar 

  • Howell LL, Cunningham KA (2015) Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol rev 67:176–197

    Article  PubMed  PubMed Central  Google Scholar 

  • Howell LL, Fantegrossi WE (2009) Intravenous drug self-administration in nonhuman primates. In: Buccafusco JJ (ed) Methods of behavior analysis in neuroscience, 2nd edn. CRC Press/Taylor & Francis, Boca Raton (FL) Chapter 9

    Google Scholar 

  • Howell LL, Negus SS (2014) Monoamine transporter inhibitors and substrates as treatments for stimulant abuse. Adv Pharmacol 69:129–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howell LL, Wilcox KM (2001) Intravenous drug self-administration in nonhuman primates. In: Buccafusco JJ (ed) Methods of behavior analysis in neuroscience. CRC Press; Boca Raton, FL, pp 91–110.

  • Howell LL, Wilcox KM (2002) Functional imaging and neurochemical correlates of stimulant self-administration in primates. Psychopharmacology 163:352–361

    Article  CAS  PubMed  Google Scholar 

  • Katz JL, Higgins ST (2003) The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology 168:21–30

    Article  CAS  PubMed  Google Scholar 

  • Kirkland Henry P, Davis M, Howell LL (2009) Effects of cocaine self-administration history under limited and extended access conditions on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys. Psychopharmacology 205:237–247

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, LeMoal M (2006) Neurobiology of addiction. Elsevier, London

    Google Scholar 

  • Manvich DF, Kimmel HL, Cooper DA, Howell LL (2012a) The serotonin 2C receptor antagonist SB 242084 exhibits abuse-related effects typical of stimulants in squirrel monkeys. J Pharmacol Exp Ther 342:761–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manvich DF, Kimmel HL, Howell LL (2012b) Effects of serotonin 2C receptor agonists on the behavioral and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 341:424–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin JR, Bös M, Jenck F, Moreau J, Mutel V, Sleight AJ, Wichmann J, Andrews JS, Berendsen HH, Broekkamp CL, Ruigt GS, Köhler C, Delft AM (1998) 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 286:913–924

  • Martin-Soelch C, Leenders KL, Chevalley A-F, Missimer J, Kunig G, Magyar S, Mino A, Schultz W (2001) Reward mechanisms in the brain and their role in dependence: evidence from neurophysiological and neuroimaging studies. Brain res rev 36:139–149

    Article  CAS  PubMed  Google Scholar 

  • Murnane KS, Fantegrossi WE, Godfrey JR, Banks ML, Howell LL (2010) Endocrine and neurochemical effects of 3,4-methylenedioxymethamphetamine and its stereoisomers in rhesus monkeys. J Pharmacol Exp Ther 334:642–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murnane KS, Kimmel HL, Rice KC, Howell LL (2012) The neuropharmacology of prolactin secretion elicited by 3,4-methylenedioxymethamphetamine (“ecstasy”): a concurrent microdialysis and plasma analysis study. Horm Behav 61:181–190

    Article  CAS  PubMed  Google Scholar 

  • Murnane KS, Winschel J, Schmidt KT, Stewart LM, Rose SJ, Cheng K et al (2013) Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates. J Neurosci 33:13367–13374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Navailles S, Moison D, Cunningham KA, Spampinato U (2008) Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine. Neuropsychopharmacology 33:237–246

    Article  CAS  PubMed  Google Scholar 

  • Neelamegam R, Hellenbrand T, Schroeder FA, Wang C, Hooker JM (2014) Imaging evaluation of 5HT2C agonists, [(11)C]WAY-163909 and [(11)C]vabicaserin, formed by Pictet-Spengler cyclization. J med Chem 57:1488–1494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neisewander JL, Acosta JI (2007) Stimulation of 5-HT2C receptors attenuates cue and cocaine-primed reinstatement of cocaine-seeking behavior in rats. Behav Pharmacol 18:791–800

    Article  CAS  PubMed  Google Scholar 

  • Perez Diaz M, Andersen ML, Rice KC, Howell LL. (2017) Combined serotonin 5-HT2CR agonist and 5-HT2AR antagonist administration attenuates the effects of methamphetamine self-administration on actigraphy-based sleep parameters in rhesus monkeys. Submitted.

  • Rüedi-Bettschen D, Spealman RD, Platt DM (2015) Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys by direct and indirect activation of 5-HT2C receptors. Psychopharmacology 232:2959–2968

    Article  PubMed  PubMed Central  Google Scholar 

  • Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275:1593–1599

    Article  CAS  PubMed  Google Scholar 

  • Spealman RD, Goldberg SR (1978) Drug self-administration by laboratory animals: control by schedules of reinforcement. Annu rev Pharmacol Toxicol 18:313–339

    Article  CAS  PubMed  Google Scholar 

  • Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shamma H, Smith B, Chalmers D, Behan D (2008) Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 325:577–587

    Article  CAS  PubMed  Google Scholar 

  • Watanabe M, Cromwell HC, Tremblay L, Hollerman JR, Hikosaka K, Schultz W (2001) Behavioral reactions reflecting differential reward expectations in monkeys. Exp Brain res 140:511–518

    Article  CAS  PubMed  Google Scholar 

  • Wilcox KM, Kimmel HL, Lindsey KP, Votaw JR, Goodman MM, Howell LL (2005) In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys. Synapse 58:220–228

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Lisa Neidert, Juliet Brown, Marisa Olsen, Cydney Eisenberg, Melis Odabas-Geldiay, Amanda Spielman, and Hannah Shields for their excellent assistance with the experiments. This research was supported by USPHS Grants DA10344 (LLH), DA031246 (LLH) and ODP51OD11132 (Yerkes National Primate Research Center), AFIP (LFB) and FAPESP Grants 2015/16109-7 (LFB), and 2015/25482-3 (LFB). The authors declare no conflict of interest.

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Author notes

  1. Laís F. Berro and Maylen Perez Diaz contributed equally to the study

Authors and Affiliations

  1. Yerkes National Primate Research Center, Emory University, 954 Gatewood Road N.E, Atlanta, GA, 30329, USA

    Laís F. Berro, Maylen Perez Diaz, Eric Maltbie & Leonard L. Howell

  2. Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil

    Laís F. Berro

  3. Department of Psychiatry and Behavioral Science, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road N.E, Atlanta, GA, 30329, USA

    Laís F. Berro, Maylen Perez Diaz, Eric Maltbie & Leonard L. Howell

Authors
  1. Laís F. Berro
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  2. Maylen Perez Diaz
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  3. Eric Maltbie
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  4. Leonard L. Howell
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Correspondence to Leonard L. Howell.

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Berro, L.F., Perez Diaz, M., Maltbie, E. et al. Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys. Psychopharmacology 234, 2607–2617 (2017). https://doi.org/10.1007/s00213-017-4653-2

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  • DOI: https://doi.org/10.1007/s00213-017-4653-2

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