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增强剂的价值，包括脑刺激奖励(BSR)、美味的食物和滥用的药物，如可卡因，部分是通过调节包括多巴胺在内的神经递质水平(Gardner，2005)。这项建议将调查伴随着大麻类受体(CB1)拮抗剂良好记录的抗复发作用的神经生物学机制(Fattore等人，2007年)。我们先前的研究表明，在BSR过程中，放电和亚秒多巴胺释放的一致变化发生在发出奖赏可获得性信号的线索中，并通过D1受体的激活在功能上联系在一起(Cheer等人，2007a)。我们还表明，由不同类别的滥用药物(定性上类似于在BSR和食物寻找中观察到的药物)引起的亚秒多巴胺的增加，可以通过给予大麻素CB1受体拮抗剂利莫那班来统一抑制。鉴于这些发现，我们提出了四个实验来检查利莫那班可能通过增强消退学习来增强消退和防止复发的机制。第一个实验将评估在消失学习的特定时间，CB1受体阻断后，线索诱导的伏核(NAC)壳内强化特异性细胞放电和亚秒多巴胺释放，以检查内源性大麻素介导的获得或巩固效应是否对消退反应的恢复产生负面影响。在实验2中将使用相同的方案来恢复高适口性食物的寻找(Ward等人，2007年)。这将澄清BSR和觅食之间的线索编码是否相似，以及它的消亡和恢复是否需要共同的CB1受体介导的机制。实验3和实验4将确定抑制的伏隔亚秒多巴胺释放、单一单位和整体编码是否伴随着CB1受体拮抗剂介导的在线索诱发的可卡因寻找恢复期间(De Vries等人，2001年)的消退恢复(De Vries等人，2001年)，在产生“渴望的潜伏期”效应(Grimm等人，2001年)之后。考虑到最近的临床证据表明，利莫那班可促进戒烟及其对复吸其他滥用药物和食物摄取(肥胖)的潜在有益影响，更清楚地了解内源性大麻素在复吸滥用药物以及自然回报方面的神经生物学作用，对于开发这些疾病的新治疗方法至关重要。因此，通过研究多巴胺能和内源性大麻素信号在消退学习过程中的相互作用，本提议可能会对药物成瘾和复发的发病机制有新的见解。 与公共卫生相关：治疗药物滥用的主要问题之一是在长期戒毒后，对药物的渴求和对环境诱因的寻求重新抬头，即通常所说的复发。临床经验表明，在成瘾患者的危机干预、戒毒、稳定和减少伤害方面，几乎没有经过验证的有效方法。通过在广泛的成瘾物质中使用具有良好治疗价值的新的药理学工具，将更好地理解在药物成瘾和依赖治疗中引发复发的神经生物学机制。

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.