Department of Psychology, Queen's University, 62 Arch St., Kingston ON, Canada K7L 3N6.
J Pharmacol Exp Ther. 2010 Nov;335(2):506-15. doi: 10.1124/jpet.110.171348. Epub 2010 Aug 19.
Dopamine receptors play a critical role in reward-related learning, but receptor subtypes may be differentially involved. D2-preferring receptor antagonists, e.g., haloperidol, attenuate acquisition of cocaine-conditioned motor activity at doses that fail to block expression. We compared haloperidol [4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one] with the D3 receptor-preferring antagonist 2,3-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4] triazol-3-yisulfanyl)-propyl]-piperazin-1-y1}-pyrimidine hydrochloride (ABT-127), given at D3 receptor-selective doses [i.e., no displacement of [(3)H]3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide binding, no effects on γ-butyrolactone-induced striatal l-3,4-dihydroxyphenylalanine; haloperidol accumulation; no attenuation of apomorphine-induced stereotypy]. We hypothesized that haloperidol and ABT-127 will produce a doubly dissociable effect on acquisition versus expression of cocaine-conditioned activity. Rats received three 1-h habituation sessions to activity monitors followed by three 1-h cocaine (10 mg/kg) conditioning sessions. The expression phase (no cocaine injections) took place 48 h later. Haloperidol (50 μ/kg) given during the conditioning phase blocked the acquisition of conditioned activity but failed to block the expression of conditioning when given on the test day. In contrast, ABT-127 (1.0 mg/kg), when given during conditioning, failed to block the acquisition of conditioned activity but blocked the expression of conditioning when administered on the test day. Results suggest that D2 receptors are more critically involved in acquisition than initial expression and D3 receptors are more critically involved in expression than acquisition of conditioned activity based on cocaine.
多巴胺受体在与奖励相关的学习中起着关键作用，但受体亚型可能会有不同的参与。D2 受体偏好拮抗剂，如氟哌啶醇，在不能阻断表达的剂量下，减弱可卡因条件性运动活动的获得。我们比较了氟哌啶醇[4-[4-(4-氯苯基)-4-羟基-1-哌啶基]-1-(4-氟苯基)-1-丁酮]与 D3 受体偏好拮抗剂 2,3-二-叔丁基-6-{4-[3-(4,5-二甲基-4H-[1,2,4]三唑-3-基硫代)-丙基]-哌嗪-1-基}-嘧啶盐酸盐（ABT-127），在 D3 受体选择性剂量下给药[即，（3）H]3,5-二氯-N-[[（2S）-1-乙基-2-吡咯烷基]甲基]-2-羟基-6-甲氧基苯甲酰胺结合无置换，γ-丁内酯诱导的纹状体 l-3,4-二羟基苯丙氨酸无影响；氟哌啶醇积累；阿扑吗啡诱导刻板行为无减弱]。我们假设氟哌啶醇和 ABT-127 将对可卡因条件性活动的获得与表达产生双重可分离的影响。大鼠接受了三个 1 小时的适应期到活动监测器，然后接受了三个 1 小时的可卡因（10mg/kg）条件期。表达阶段（无可卡因注射）发生在 48 小时后。氟哌啶醇（50μg/kg）在条件期给予时阻断了条件性活动的获得，但在测试日给予时未能阻断条件性表达。相比之下，ABT-127（1.0mg/kg）在条件期给予时未能阻断条件性活动的获得，但在测试日给予时阻断了条件性表达。结果表明，基于可卡因，D2 受体在获得过程中比初始表达更关键，而 D3 受体在表达过程中比获得条件性活动更关键。
