Cannabinoid Receptor Mechanisms in Accumbal Encoding of Extinction Learning

已经提出，内源性大麻素有助于评估各种大麻素，包括 大脑刺激奖励（BSR），美味的食物和滥用的药物，如可卡因，部分通过调节 神经递质水平，包括多巴胺（Gardner，2005）。这项提案将研究神经生物学 伴随大麻素受体（CB 1）的抗复发作用的机制 拮抗剂（Fattore等，2007年）。我们先前的研究表明，在放电和亚秒级的同步变化， 在BSR期间，多巴胺释放发生在信号奖励可用性的线索处，并通过D1在功能上相关联 受体活化（Cheer等人，2007年a）。我们还表明，亚秒多巴胺的增加引起了 不同类别的药物滥用（定性类似于在BSR和食物寻求中观察到的药物滥用）， 通过施用大麻素CB 1受体拮抗剂利莫那班而均匀地抑制。鉴于这些 研究结果，我们提出了四个实验来研究利莫那班可能增强的机制， 灭绝学习，以加强灭绝和防止复发。第一个实验将评估强化- 在提示过程中，特定的细胞放电和亚秒多巴胺释放在丘脑核（NAc）的外壳中， 在消退学习过程中的特定时间，CB 1受体阻断后诱导恢复到BSR， 检查内源性大麻素介导的对获得或巩固的影响是否对提取产生负面影响 灭绝反应。在实验2中将使用相同的方案来恢复高浓度。 适口性食物寻求（Ward等人，2007年）。这将澄清是否提示编码是类似的BSR和食物之间 寻求和它的灭绝和检索是否需要共同的CB 1受体介导的机制。 实验3和4将确定是否衰减的多巴胺亚秒释放，单单位 和整体编码伴随CB 1受体拮抗剂介导的灭绝恢复增强 在可卡因寻求的线索诱发的恢复期间（De弗里斯等人，2001年），禁欲期后， 产生“渴望的孵化”效应（Grimm等人，2001年）。考虑到最近的临床证据， 利莫那班诱导的增强戒烟效果及其对复吸的潜在有益作用 其他药物滥用和食物摄入（肥胖），更清楚地了解神经生物学作用， 内源性大麻素对滥用药物的复发以及对自然回报的影响至关重要， 对于这些疾病的新疗法的发展。因此，通过对 在消退学习过程中多巴胺能和内源性大麻素信号之间的相互作用， 本建议可能会导致对药物成瘾和复吸的发病机制的新见解。

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.