1. Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats.
- Author
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Vorel SR, Ashby CR Jr, Paul M, Liu X, Hayes R, Hagan JJ, Middlemiss DN, Stemp G, and Gardner EL
- Subjects
- Animals, Behavior, Animal drug effects, Brain physiopathology, Catalepsy chemically induced, Catalepsy physiopathology, Cocaine administration & dosage, Cocaine-Related Disorders physiopathology, Conditioning, Operant drug effects, Dopamine Antagonists adverse effects, Dose-Response Relationship, Drug, Electric Stimulation, Electrodes, Implanted, Haloperidol adverse effects, Haloperidol therapeutic use, Male, Nitriles adverse effects, Nitriles therapeutic use, Quinolines adverse effects, Quinolines therapeutic use, Rats, Rats, Long-Evans, Rats, Sprague-Dawley, Receptors, Dopamine D2 metabolism, Receptors, Dopamine D3, Reinforcement, Psychology, Secondary Prevention, Self Administration, Spatial Behavior drug effects, Brain drug effects, Cocaine-Related Disorders drug therapy, Dopamine Antagonists therapeutic use, Dopamine D2 Receptor Antagonists, Reward, Tetrahydroisoquinolines
- Abstract
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.
- Published
- 2002