The International Journal of Neuropsychopharmacology

Research Article

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

Jack Bergmana1 c1, Rebecca A. Roofa2 *, Cheryse A. Furmana2 *, Jennie L. Conroya2, Nancy K. Melloa1, David R. Sibleya2 and Phil Skolnicka3

a1 Harvard Medical School-McLean Hospital, Alcohol and Drug Abuse Research Center, Belmont, MA, USA

a2 Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA

a3 Division of Pharmacotherapies and Medical Consequences of Drug Abuse, NIDA, National Institutes of Health, Bethesda, MD, USA

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.

(Received February 09 2012)

(Reviewed February 25 2012)

(Revised May 03 2012)

(Accepted May 23 2012)

(Online publication July 25 2012)

Key words

  • Buspirone;
  • cocaine addiction;
  • D3 receptor antagonist;
  • D4 receptor antagonist;
  • i.v. self-administration;
  • medications development

Correspondence:

c1 Address for correspondence: J. Bergman, PhD, Harvard Medical School-McLean Hospital, 115 Mill Street, Belmont, MA 02478-9106, USA. Tel.: +1 617 855 2464 Fax: +1 617 855 2417 Email: jbergman@hms.harvard.edu

Footnotes

*  These authors contributed equally to this work.