Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30322, USA.
J Neurosci. 2013 Aug 14;33(33):13367-74. doi: 10.1523/JNEUROSCI.1437-13.2013.
Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways.
两种最常用于研究实验室动物药物滥用相关效应的方法是静脉内药物自我给药和先前由药物给药维持的已灭绝行为的复现。静脉内自我给药被广泛接受为模型持续的药物摄取行为，而复现程序被接受为模型在戒断后对药物摄取的复发。先前的研究表明，5-HT2A 受体拮抗剂可减弱可卡因维持的行为的复现，但不能减弱啮齿动物的可卡因自我给药。尽管可卡因的滥用相关效应与大脑多巴胺系统密切相关，但以前的研究尚未确定这种分离是否与多巴胺神经传递的差异调节有关。为了阐明这种现象的神经药理学和神经解剖学机制，我们评估了选择性 5-HT2A 受体拮抗剂 M100907 对恒河猴（Macaca mulatta）静脉内可卡因自我给药和药物及线索诱发复现的影响。在不同的研究对象中，我们使用体内微透析评估了 5-HT2A 受体在可卡因诱导的伏隔核（n = 4）和尾状核（n = 5）中多巴胺溢出中的作用。与先前的研究一致，M100907（0.3mg/kg，肌内注射）显著减弱了药物和线索诱发的复现，但在一系列维持剂量下对可卡因自我给药没有显著影响。重要的是，M100907（0.3mg/kg，肌内注射）减弱了可卡因（1.0mg/kg，静脉内）诱导的尾状核多巴胺溢出，但对伏隔核没有影响。这些数据表明，可卡因的重要滥用相关效应是由不同的纹状体多巴胺投射途径介导的。
