Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats.
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.
Vorel
Stanislav R
SR
Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
Ashby
Charles R
CR
Paul
Mousumi
M
Liu
Xinhe
X
Hayes
Robert
R
Hagan
Jim J
JJ
Middlemiss
Derek N
DN
Stemp
Geoffrey
G
Gardner
Eliot L
EL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002375:Catalepsy / Q000139:chemically induced / Q000503:physiopathology; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D003216:Conditioning, Operant / Q000187:drug effects; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D006220:Haloperidol / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3; D012054:Reinforcement, Psychology; D012201:Reward; D055502:Secondary Prevention; D012646:Self Administration; D013037:Spatial Behavior / Q000187:drug effects; D044005:Tetrahydroisoquinolines
D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493595:Drd3 protein, rat; D009570:Nitriles; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D003042:Cocaine; D006220:Haloperidol