Skip to main content
×
Home
    • Aa
    • Aa
  • The International Journal of Neuropsychopharmacology, Volume 16, Issue 2
  • March 2013, pp. 445-458

Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors

  • Jack Bergman (a1), Rebecca A. Roof (a2), Cheryse A. Furman (a2), Jennie L. Conroy (a2), Nancy K. Mello (a1), David R. Sibley (a2) and Phil Skolnick (a3)
  • DOI: http://dx.doi.org/10.1017/S1461145712000661
  • Published online: 25 July 2012
Abstract
Abstract

Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D1 nor D2 receptor antagonists have proven effective, medications acting at two other potential targets, D3 and D4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D3 and D4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D3 and D4 receptors (∼98 and ∼29 nm respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D3 and D4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose–effect function for cocaine-maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction.

Copyright
Corresponding author
Address for correspondence: J. Bergman, PhD, Harvard Medical School-McLean Hospital, 115 Mill Street, Belmont, MA 02478-9106, USA. Tel.: +1 617 855 2464Fax: +1 617 855 2417Email: jbergman@hms.harvard.edu
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

AL Anderson , MS Reid , SH Li , T Holmes , . (2009). Modafinil for the treatment of cocaine dependence. Drug and Alcohol Dependence 104, 133139.

AK Banala , BA Levy , SS Khatri , CA Furman , . (2011). N-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl) piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity. Journal of Medicinal Chemistry 54, 581594.

J Bergman , JB Kamien , RD Spealman (1990). Antagonism of cocaine self-administration by selective dopamine D1 and D2 antagonists. Behavioural Pharmacology 1, 355363.

LH Brauer , H de Wit (1996). Subjective responses to d-amphetamine alone and after primozide pretreatment in normal, healthy volunteers. Biological Psychiatry 39, 2632.

D Brody , LA Adler , T Kim , B Angrist , . (1990). Effects of buspirone in seven schizophrenic subjects. Journal of Clinical Psychopharmacology 10, 6869.

F Bruno (1989). Buspirone in the treatment of alcoholic patients. Psychopathology 22 (Suppl. 1), 4959.

PM Callahan , KA Cunningham (1997). Modulation of the discriminative stimulus properties of cocaine: comparison of the effects of fluoxetine with 5-HT1A and 5-HT1B receptor agonists. Neuropharmacology 36, 373381.

P Czobor , P Skolnick (2011). The secrets of a successful clinical trial: compliance, compliance, and compliance. Molecular Interventions 11, 107110.

RC Dockens , DE Salazar , IE Fulmor , R Croop (2006). Pharmacokinetics of a newly identified metabolite of buspirone following administration of buspirone over its therapeutic dose range. Journal of Clinical Pharmacology 46, 13081312.

RC Dockens , AQ Tran , J Zeng , R Croop (2007). Pharmacokinetics of 6-hydroxybuspirone and its enantiomers administered individually or following buspirone administration in humans. Biopharmaceutics and Drug Disposition 28, 393402.

A Elkashef , PJ Fudala , L Gorgon , SH Li , . (2006). Double-blind, placebo-controlled trial of selegiline transdermal system (STS) for the treatment of cocaine dependence. Drug and Alcohol Dependence 85, 191197.

RE Gammans , RF Mayol , JA LaBudde (1986). Metabolism and disposition of buspirone. American Journal of Medicine 80 (Suppl. 3B), 4151.

DC Goff , KK Midha , AW Brotman , S McCormick , . (1991). An open trial of buspirone added to neuroleptics in schizophrenic patients. Journal of Clinical Psychopharmacology 11, 193197.

LH Gold , RL Balster (1992). Effects of buspirone and gepirone on IV cocaine self-administration in rhesus monkeys. Psychopharmacology 108, 289294.

M Haney , AS Ward , RW Foltin , MW Fischman (2001). Effect of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration in humans. Psychopharmacology 155, 330337.

MW Jann (1988). Buspirone: an update on a unique anxiolytic agent. Pharmacotherapy 8, 100116.

R Kahn , K Biswas , AR Childress , S Shoptaw , . (2009). Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals. Drug and Alcohol Dependence 103, 5964.

JB Kamien , WL Woolverton (1990). Buspirone blocks the discriminative stimulus effects of apomorphine in monkeys. Pharmacology Biochemistry and Behavior 35, 117120.

M Kotler , H Cohen , R Segman , I Gritsenko , . (1997). Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects. Molecular Psychiatry 2, 251254.

NS Kula , RJ Baldessarini , JW Kebabian , JL Neumeyer (1994). S-(+)-aporphines are not selective for human D3 dopamine receptors. Cell and Molecular Neurobiology 14, 185191.

M Laucht , K Becker , D Blomeyer , MH Schmidt (2007). Novelty seeking involved in mediating the association between the dopamine D4 receptor gene exon III polymorphism and heavy drinking in male adolescents: results from a high-risk community sample. Biological Psychiatry 61, 8792.

B Le Foll , JC Schwartz , P Sokoloff (2000). Dopamine D3 receptor agents as potential new medications for drug addiction. European Psychiatry 15, 140146.

B Le Foll , A Gallo , Y Le Strat , L Lu , . (2009). Genetics of dopamine receptors and drug addiction: a comprehensive review. Behavioural Pharmacology 20, 117.

JM Lusher , C Chandler , D Ball (2001). Dopamine D4 receptor gene (DRD4) is associated with novelty seeking (NS) and substance abuse: the saga continues. Molecular Psychiatry 6, 497499.

TS Malec , EA Malec , M Dongier (1996). Efficacy of buspirone in alcohol dependence: a review. Alcoholism: Clinical and Experimental Research 20, 853858.

FG Moeller , DM Dougherty , ES Barratt , JM Schmitz , . (2001). The impact of impulsivity on cocaine use and retention in treatment. Journal of Substance Abuse Treatment 21, 193198.

CP Müller , RJ Carey , JP Huston , MA De Souza Silva (2007). Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors. Progress in Neurobiology 81, 133178.

MA Nader , WL Woolverton (1994). Blockade of the discriminative stimulus effects of d-amphetamine in rhesus monkeys with serotonin 5-HT(1A) agonists. Behavioural Pharmacology 5, 591598.

Y Namkung , C Dipace , E Urizar , JA Javitch , . (2009). G protein-coupled receptor kinase-2 constitutively regulates D2 dopamine receptor expression and signaling independently of receptor phosphorylation. Journal of Biological Chemistry 284, 3410334115.

E Nann-Vernotica , EC Donny , GE Bigelow , SL Walsh (2001). Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine. Psychopharmacology 155, 338347.

SS Negus , NK Mello (2003). Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys. Drug and Alcohol Dependence 70, 3952.

NG Schneider , RE Olmstead , C Steinberg , K Sloan , . (1996). Efficacy of buspirone in smoking cessation: a placebo-controlled trial. Clinical Pharmacology and Therapeutics 60, 568575.

SK Shenoy , RJ Lefkowitz (2011). β-arrestin-mediated receptor trafficking and signal transduction. Trends in Pharmacological Sciences 32, 521533.

MA Sherer , KM Kumor , JH Jaffe (1989). Effects of intravenous cocaine are partially attenuated by haloperidol. Psychiatry Research 27, 117125.

P Sirota , B Epstein , R Benatov , M Sousnostzky , . (2001). An open study of buspirone augmentation of neuroleptics in patients with schizophrenia. Journal of Clinical Psychopharmacology 21, 454455.

T Sumiyoshi , S Park , K Jayathilake , A Roy , . (2007). Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophrenia Research 95, 158168.

SR Wachtel , A Ortengren , H de Wit (2002). The effects of acute haloperidol or risperidone on subjective responses to methamphetamine in healthy volunteers. Drug and Alcohol Dependence 68, 2333.

H Wong , RC Dockens , L Pajor , S Yeola , . (2007). 6-hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats. Drug Metabolism and Disposition 35, 13871392.

ZX Xi , JG Gilbert , AC Pak , CR Ashby Jr., . (2005). Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats. European Journal of Neuroscience 21, 34273438.

Y Yan , A Pushparaj , Y Le Strat , I Gamaleddin , . (2012). Blockade of dopamine D4 receptors attenuates reinstatement of extinguished nicotine-seeking behavior in rats. Neuropsychopharmacology 37, 685696.

X Zhao , A Jones , KR Olsen , K Peng , . (2008). A homogeneous enzyme fragment complementation-based beta-arrestin translocation assay for high-throughput screening of G-protein-coupled receptors. Journal of Biomolecular Screening 13, 737747.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords: