Cannabinoid Receptor Mechanisms in Accumbal Encoding of Extinction Learning

描述（由申请人提供）：有人提出，内源性大麻素有助于各种强化物的评估，包括脑刺激奖励（BSR），非常美味的食物和滥用药物，如可卡因，部分通过调节包括多巴胺在内的神经递质水平（Gardner, 2005）。该提案将研究伴随大麻素受体（CB1）拮抗剂抗复发作用的神经生物学机制（fatore等，2007）。我们之前的研究表明，放电和亚秒多巴胺释放的同步变化发生在BSR过程中奖励可用性的信号上，并通过D1受体激活在功能上联系在一起（Cheer等，2007a）。我们还表明，不同类别的药物滥用引起的亚秒多巴胺的增加（在质量上类似于BSR和寻找食物中观察到的）被大麻素CB1受体拮抗剂利莫那班所抑制。鉴于这些发现，我们提出了四个实验来研究利莫那班可能增强消退学习以增强消退和预防复发的机制。第一个实验将评估CB1受体阻断后，在消退学习的特定时间，线索诱导的BSR恢复过程中，伏隔核（NAc）的强化特异性细胞放电和亚秒多巴胺释放，以检验内源性大麻素介导的获取或巩固效应是否对消退反应的恢复产生负面影响。实验2将使用相同的方案来恢复高适口性食物寻找（Ward et al., 2007）。这将阐明BSR和食物寻找之间的线索编码是否相似，以及它的消失和恢复是否需要共同的CB1受体介导的机制。实验3和4将确定，在线索诱发的可卡因寻求恢复过程中，CB1受体拮抗剂介导的消失恢复增强是否伴随着伏隔亚秒多巴胺释放的减弱，单单位和集合编码（De Vries等，2001），在产生“渴望潜伏期”效应的戒断期之后（Grimm等，2001）。考虑到最近的临床证据表明，利莫那班诱导的戒烟效果增强，以及它对再次滥用其他药物和减少食物摄入（肥胖）的潜在有益影响，更清楚地了解内源性大麻素对再次滥用药物以及自然奖励的神经生物学作用，对于开发这些疾病的新疗法至关重要。因此，通过研究多巴胺能和内源性大麻素信号在消失学习过程中的相互作用，本研究可能会对药物成瘾和复发的发病机制产生新的见解。

DESCRIPTION (provided by applicant): It has been proposed that endogenous cannabinoids contribute to the valuation of various reinforcers including brain stimulation reward (BSR), highly palatable food and abused drugs such as cocaine, in part by modulating neurotransmitter levels including dopamine (Gardner, 2005). This proposal will investigate the neurobiological mechanisms that accompany the well-documented anti-relapse effects of cannabinoid receptor (CB1) antagonists (Fattore et al., 2007). Our prior studies showed that coincident changes in firing and subsecond dopamine release occur at cues signaling reward availability during BSR and are functionally linked via D1 receptor activation (Cheer et al., 2007a). We have also shown that increases in subsecond dopamine elicited by drugs of abuse of different classes (qualitatively similar to those observed in BSR and food seeking) are uniformly inhibited by administration of the cannabinoid CB1 receptor antagonist rimonabant. Given these findings, we propose four experiments to examine the mechanisms through which rimonabant may potentiate extinction learning to enhance extinction and prevent relapse. The first experiment will evaluate reinforcement- specific cell firing and subsecond dopamine release in the shell of the nucleus accumbens (NAc) during cue- induced reinstatement to BSR following CB1 receptor blockade at specific times during extinction learning, to examine if endogenous cannabinoid-mediated effects on acquisition or consolidation negatively affect retrieval of the extinction response. An identical protocol will be utilized in experiment 2 for reinstatement of high palatability food seeking (Ward et al., 2007). This will clarify if cue-encoding is similar between BSR and food seeking and whether its extinction and retrieval requires common CB1 receptor-mediated mechanisms. Experiments 3 and 4 will determine whether attenuated accumbal subsecond dopamine release, single-unit and ensemble encoding accompanies CB1 receptor antagonist-mediated enhancement of extinction retrieval during cue-evoked reinstatement of cocaine seeking (De Vries et al., 2001), following abstinence periods that produce an "incubation of craving" effect (Grimm et al., 2001). Considering recent clinical evidence of rimonabant-induced enhanced cessation of the use of tobacco and its potential beneficial effects on relapse to other drugs of abuse and on food intake (obesity), a clearer understanding of the neurobiological role of endogenous cannabinoids on relapse to abused drugs, as well as to natural rewards, is paramount with respect to the development of new treatments for these diseases. Therefore, through the examination of interactions between dopaminergic and endogenous cannabinoid signaling during extinction learning, the present proposal will likely lead to new insights on the pathogenesis of drug addiction and relapse. PUBLIC HEALTH RELEVANCE: One of the major problems in the treatment of drug abuse is the renewal of drug craving and seeking upon environmental triggers, commonly known as relapse, after protracted abstinence periods. Clinical experience has reported the availability of very few proven effective approaches for use in crisis intervention, detoxification, stabilization and harm reduction in addicted patients. By employing new pharmacological tools with promising therapeutic value in a broad spectrum of addictive substances, a better understanding of the neurobiological mechanisms triggering relapse in the treatment of drug addiction and dependence will be gained.