Skip to main content

Advertisement

Log in

Effects of buspirone and the dopamine D3 receptor compound PG619 on cocaine and methamphetamine self-administration in rhesus monkeys using a food-drug choice paradigm

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The dopamine (DA) D2 and D3 receptors have been associated with cocaine abuse. A recent study with the D3 receptor (D3R) partial agonist PG619 found that it attenuated cocaine-induced reinstatement and the D2-like receptor antagonist buspirone has shown positive outcomes in two studies of cocaine abuse in monkeys. However, a recent clinical trial indicated that buspirone did not improve abstinence in treatment-seeking cocaine abusers.

Objective

The objective of the study was to examine PG619 and buspirone under a food-drug choice paradigm in order to better model the clinical findings. In addition, we extended the characterization of both compounds to include methamphetamine (MA) self-administration (SA).

Methods

Six adult male rhesus monkeys were trained to respond under a concurrent food (1.0-g pellets) and drug (0.01–0.3 mg/kg/injection cocaine or MA) choice paradigm in which complete SA dose-response curves were determined each session (N = 3/group). Monkeys received 5 days of treatment with either PG619 (0.1–3.0 mg/kg, i.v.) or buspirone (0.01–1.0 mg/kg, i.m.). In a follow-up study, the SA doses were reduced (0.003–0.1 mg/kg/injection) to increase reinforcement frequency and buspirone was retested.

Results

PG619 did not affect cocaine or MA choice, while buspirone increased low-dose cocaine choice. Changing the SA doses increased the number of reinforcers received each session, but buspirone did not decrease drug choice.

Conclusions

Consistent with clinical findings, these results do not support the use of buspirone for psychostimulant abuse and suggest that food-drug choice paradigms may have greater predictive validity than the use of other schedules of reinforcement.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Achat-Mendes C, Platt DM, Newman AH, Spealman RD (2009) The dopamine D3 receptor partial agonist CJB 090 inhibits the discriminative stimulus but not the reinforcing or priming effects of cocaine in squirrel monkeys. Psychopharmacology 206:73–84

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baladi MG, Newman AH, France CP (2014) Feeding condition and the relative contribution of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine in rats. Psychopharmacology 231:581–591

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Banks ML, Negus SS (2012) Preclinical determinants of drug choice under concurrent schedules of drug self-administration. Adv Pharmacol Sci 2012:281768

    PubMed Central  PubMed  Google Scholar 

  • Bennett BA, Hollingsworth CK, Martin RS, Harp JJ (1993) Methamphetamine-induced alterations in dopamine transporter function. Brain Res 782:219–227

    Article  Google Scholar 

  • Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P (2013) Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors. Int J Neuropsychopharmacol 16:445–458

    Article  CAS  PubMed  Google Scholar 

  • Blaylock BL, Gould RW, Banala A, Grundt P, Luedtke RR, Newman AH, Nader MA (2011) Influence of cocaine history on the behavioral effects of dopamine D3 receptor-selective compounds in monkeys. Neuropsychopharmacology 36:1104–1113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Boileau I, Payer D, Houle S, Behzadi A, Rusjan PM, Tong J, Wilkins D, Selby P, George TP, Zack M, Furukawa Y, McCluskey T, Wilson AA, Kish SJ (2012) Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study. J Neurosci 32:1353–1359

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Coffin PO, Santos GM, Das M, Santos DM, Huffaker S, Matheson T, Gasper J, Vittinghoff E, Colfax GN (2013) Aripiprazole for the treatment of methamphetamine dependence: a randomized, double-blind, placebo-controlled trial. Addiction 108:751–761

    Article  PubMed Central  PubMed  Google Scholar 

  • Czoty PW, Nader MA (2013) Effects of dopamine D2/D3 receptor ligands on food-cocaine choice in socially housed male cynomolgus monkeys. J Pharmacol Exp Ther 344:329–338

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Czoty PW, McCabe C, Nader MA (2005) Effects of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on cocaine choice in cynomolgus. Behav Pharmacol 16:187–191

    Article  CAS  PubMed  Google Scholar 

  • Grundt P, Prevatt KM, Cao J, Taylor J, Floresca CZ, Choi J-K, Jenkins BG, Luedtke RR, Newman AH (2007) Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-butyl)-aryl-carboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: potential substance abuse therapeutic agents. J Med Chem 50:4135–4146

    Article  CAS  PubMed  Google Scholar 

  • Haile CN, Kosten TR (2013) Pharmacotherapy for stimulant-related disorders. Curr Psychiatry Rep 15:415

    Article  PubMed  Google Scholar 

  • Haney M, Spealman R (2008) Controversies in translational research: drug self-administration. Psychopharmacology 199:403–419

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Haney M, Rubin R, Fotin RW (2011) Aripiprazole maintencance increases smoked cocaine self-administration in humans. Psychopharmacology 216:379–387

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Heidbreder C (2013) Rationale in support of the use of selective dopamine D3 receptor antagonists for the pharmacotherapeutic management of substance use disorders. Naunyn-Schmiedeberg’s Arch Pharmacol 386:167–176

    Article  CAS  Google Scholar 

  • Heidbreder CA, Newman AH (2010) Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann NY Acad Sci 1187:4–34

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Heyman GH (2009) Addiction: a disorder of choice. Harvard University Press, Cambridge

    Google Scholar 

  • Johnson BA, Roache JD, Ait-Daoud N, Wells LT, Wallace CL, Dawes MA, Liu L, Wang X-Q (2007) Effects of acute topiramate dosing on methamphetamine-induced subjective mood. Int J Neuropsychopharmacol 10:85–98

    Article  CAS  PubMed  Google Scholar 

  • Jones SR, Gainetdinov RR, Wightman RM, Caron MG (1998) Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci 18:1979–1986

    CAS  PubMed  Google Scholar 

  • Kampman KM, Pettinati H, Lynch KG, Dackis C, Sparkman T, Weigley C, O’Brien CP (2004) A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Dep 75:233–240

    Article  CAS  Google Scholar 

  • Koffarnus MN, Collins GT, Rice KC, Chen J, Woods JH, Winger G (2012) Self-administration of agonists selective for dopamine D2, D3, and D4 receptors by rhesus monkeys. Behav Pharmacol 23:331–338

    Article  CAS  PubMed  Google Scholar 

  • Martelle JL, Claytor R, Ross JT, Newman AH, Nader MA (2007) Effects of two novel D3-selective compounds, NGB 2904 and CJB 090, on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys. J Pharmacol Exp Ther 321:573–582

    Article  CAS  PubMed  Google Scholar 

  • Martelle SE, Nader SH, Czoty PW, John W, Duke AN, Garg PK et al. (2014) Quinpirole-elicited yawning in monkeys: Relationship with D3 receptor availability, sex differences and effects of chronic drug exposure. J Pharmacol Exp Ther 350:205–211

  • McMillen BA, Mathews RT, Sanghera MK, Shepard PD, German DC (1983) Dopamine receptor antagonism by the novel anti-anxiety drug, buspirone. J Neurosci 3:733–738

    CAS  PubMed  Google Scholar 

  • Mello NK, Fivel PA, Kohut SJ, Bergman J (2013) Effects of chronic buspirone treatment on cocaine self-administration. Neuropsychopharmacology 38:455–467

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Munzar P, Goldberg SR (2000) Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats. Psychopharmacology 148:209–216

    Article  CAS  PubMed  Google Scholar 

  • Nader MA, Barrett JE (1990) Effects of chlordiazepoxide, buspirone and serotonin receptor agonists and antagonists on responding of squirrel monkeys maintained under second-order schedules of intramuscular cocaine injection or food presentation. Drug Dev Res 20:5–17

    Article  CAS  Google Scholar 

  • Negus SS (2003) Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d-amphetamine and flupenthixol. Neuropsychopharmacology 28:919–931

    PubMed  Google Scholar 

  • Newman AH, Grundt P, Nader MA (2005) Dopamine D3 receptor partial agonists and antagonists as potential drug abuse therapeutic agents. J Med Chem 48:3664–3679

    Article  Google Scholar 

  • Newman AH, Blaylock BL, Nader MA, Bergman J, Sibley DR, Skolnick P (2012) Medication discovery for addiction: translating the dopamine D3 receptor hypothesis. Biochem Pharmacol 84:882–890

    Article  CAS  PubMed  Google Scholar 

  • Orio L, Wee S, Newman AH, Pulvirenti L, Koob GF (2010) The dopamine D3 receptor partial agonist CJB090 and antagonist PG01037 decrease progressive ratio responding for methamphetamine in rats with extended-access. Addict Biol 15:312–323

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Payer DE, Behzadi A, Kish SJ, Houle S, Wilson AA, Rusjan PM et al. (2013) Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: A positron emission tomography study with [11C]-(+)-PHNO. Neuropsychopharmacology, in press

  • Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz J, Everitt BJ, Sokoloff P (1999) Selective inhibition of cocaine-seeking behavior by a partial dopamine D3 receptor agonist. Nature 400:371–375

    Article  CAS  PubMed  Google Scholar 

  • Pulvirenti L, Koob GF (1994) Dopamine receptor agonists, partial agonists and psychostimulant addiction. Trends Pharmacol Sci 15:374–379

    Article  CAS  PubMed  Google Scholar 

  • Raiteri M, Del Carmine R, Bertollini A, Levi G (1977) Effect of sympathomimetic amines on the synaptosomal transport of noradrenaline, dopamine and 5-hydroxytryptamine. Eur J Pharmacol 41:133–143

    Article  CAS  PubMed  Google Scholar 

  • Russo SJ, Nestler EJ (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci 14:609–625

    Article  CAS  PubMed  Google Scholar 

  • SAMHSA (2013) Substance abuse and mental health services administration. Reliability of key measures in the national survey on drug use and health. Substance abuse and mental health services administration. U.S. Dept. of Health and Human Services, Rockville

    Google Scholar 

  • Sasaki JE, Tatham TA, Barrett JE (1995) The discriminative stimulus effects of methamphetamine in pigeons. Psychopharmacology 120:303–310

    Article  CAS  PubMed  Google Scholar 

  • Sinnott RS, Mach RH, Nader MA (1999) The role of dopamine D3 receptors in the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys. Drug Alcohol Dep 54:97–110

    Article  CAS  Google Scholar 

  • Skolnick P, Paul S, Weissman BA (1984) Preclinical pharmacology of buspirone hydrochloride. Pharmacotherapy 4:308–314

    CAS  PubMed  Google Scholar 

  • Sonders MS, Zhu SJ, Zahniser NR, Kavanaugh MP, Amara SG (1997) Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. J Neurosci 17:960–974

    CAS  PubMed  Google Scholar 

  • Winchell C, Rappaport BA, Roca R, Rosebraugh CJ (2012) Reanalysis of methamphetamine dependence treatment trial. CNS Neurosci Ther 18:367–368

    Article  CAS  PubMed  Google Scholar 

  • Winhusen TM, Kropp F, Lindblad R, Douaihy A, Haynes L, Hodgkins C et al. (2014) Multisite, randomized, double-blind, placebo-controlled pilot clinical trial to evaluate the efficacy of buspirone as a relapse-prevention treatment for cocaine dependence. J Clin Psychiatry, in press

  • Woolverton WL, Balster RL (1981) Effects of antipsychotic compounds in rhesus monkeys given a choice between cocaine and food. Drug Alcohol Dep 8:69–78

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Michelle Bell and Whitney Wilson for excellent technical assistance and Dr. Paul Czoty for comments on an earlier version of this manuscript. This research was supported by the National Institute on Drug Abuse grant DA012460 and NIDA-IRP. WS John is supported by T32 AA-007565.

Conflict of interest

The authors declare no conflicts of interest.

Author contributions

W.S.J. and M.A.N. designed the experiments. W.S.J. performed the behavioral studies, and analyzed the data. A.K.B synthesized PG619. The manuscript was written by W.S.J., A.H.N., and M.A.N.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael A. Nader.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

John, W.S., Banala, A.K., Newman, A.H. et al. Effects of buspirone and the dopamine D3 receptor compound PG619 on cocaine and methamphetamine self-administration in rhesus monkeys using a food-drug choice paradigm. Psychopharmacology 232, 1279–1289 (2015). https://doi.org/10.1007/s00213-014-3760-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3760-6

Keywords

Navigation