Vorel Stanislav R, Ashby Charles R, Paul Mousumi, Liu Xinhe, Hayes Robert, Hagan Jim J, Middlemiss Derek N, Stemp Geoffrey, Gardner Eliot L
Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
J Neurosci. 2002 Nov 1;22(21):9595-603. doi: 10.1523/JNEUROSCI.22-21-09595.2002.
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.
多巴胺D3受体主要定位于中脑皮质边缘多巴胺能系统，据推测其在可卡因成瘾中发挥作用。为了研究D3受体在通常被认为与可卡因成瘾特性相关的脑机制和行为中的作用，将强效选择性D3受体拮抗剂反式-N-[4-[2-(6-氰基-1,2,3,4-四氢异喹啉-2-基)乙基]环己基]-4-喹啉甲酰胺（SB-277011-A）给予实验大鼠，并评估以下指标：（1）可卡因增强的脑电刺激奖赏；（2）可卡因诱导的条件性位置偏爱；（3）可卡因引发的可卡因觅药行为的恢复。结果发现，全身注射SB-277011-A能够（1）阻断可卡因对脑电刺激奖赏的增强作用；（2）剂量依赖性地减弱可卡因诱导的条件性位置偏爱；（3）剂量依赖性地减弱可卡因引发的可卡因觅药行为的恢复。因此，D3受体阻断可减弱可卡因的奖赏效应以及可卡因诱导的觅药行为。这些数据表明D3受体在介导可卡因成瘾特性中起重要作用，并提示多巴胺D3受体阻断可能构成可卡因成瘾前瞻性药物治疗的一个新的有用靶点。
