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The Journal of Neuroscience, November 1, 2002, 22(21):9595-9603

Dopamine D₃ Receptor Antagonism Inhibits Cocaine-Seeking and Cocaine-Enhanced Brain Reward in Rats

Stanislav R. Vorel^{1, 2}, Charles R. Ashby Jr⁴, Mousumi Paul⁵, Xinhe Liu³, Robert Hayes², Jim J. Hagan⁶, Derek N. Middlemiss⁶, Geoffrey Stemp⁶, and Eliot L. Gardner^{1, 2, 3}

¹ Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, Departments of ² Neuroscience and ³ Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York 10461, ⁴ Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Saint John's University, Jamaica, New York 11439, ⁵ Eon Laboratories, Laurelton, New York 11413, and ⁶ Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex CM19 5AW, United Kingdom

The dopamine D₃ receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D₃ receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D₃ receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D₃ receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D₃ receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D₃ receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.

Key words: cocaine; addiction; dopamine; mesolimbic; mesocorticolimbic; D₃ receptor; D₃ antagonist; brain stimulation reward; BSR; self-stimulation; ICSS; conditioned place preference; CPP; self-administration; reinstatement; relapse

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22219595-09$05.00/0

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