Relapse and 5-HT2CR-PLD signaling in rat amygdala

描述（由申请人提供）：可卡因复吸可在长时间戒断后开始，以响应与吸毒相关的提示（视觉、听觉、触觉）。重复使用可卡因可能会通过篡夺通常用于加强自然奖励的学习机制来诱导关键大脑区域的长期变化（神经适应）。与可卡因相关的奖励特性和内感受性感受与环境线索有关。这种关联在临床上是重要的，因为强烈的药物渴望导致成瘾者对复发的敏感性很高，主要是对这种环境线索的反应。然而，我们仍然有一个贫穷的了解药物依赖的学习协会的分子机制。在本提案中，我们将测试的假设，即表达一个条件的行为反应，以前可卡因配对的环境需要磷脂酶D（PLD）信号在杏仁核，一个关键的大脑区域的形成和表达的联想记忆下游的5-羟色胺（5-HT）2C受体（5-HT 2CRs）。我们建议调查的需求PLD和5-HT 2CR功能可卡因诱导的条件性多动行为的表达，使用药物干预，并确定具体的杏仁核中的PLD活性的调节效果，并研究其对5-HT 2CR介导的抑制条件性多动的效果。长期记忆机制中可卡因-线索相关神经适应性的这种杏仁核特异性实验研究通过推进对与药物-环境条件关联相关的信号传导机制的基本理解和在临床前模型中针对降低复发风险进行治疗潜力的初步研究而起双重作用。

DESCRIPTION (provided by applicant): Relapse to cocaine can be initiated after long periods of abstinence in response to cues (visual, auditory, tactile) associated with drug-taking. Repeated use of cocaine induces long-term changes (neuroadaptations) in the key brain regions potentially by usurping the learning mechanisms normally used to reinforce natural rewards. The rewarding properties and interoceptive feelings linked to cocaine become associated with environmental cues. This association is clinically important since intense drug craving causing the addicts to remain highly susceptible to relapse can predominantly occur in response to such environmental cues. However, we still have a poor understanding of the molecular mechanisms underlying drug-dependent learned associations. In the present proposal, we will test the hypothesis that expression of a conditioned behavioral response to a previously cocaine-paired environment requires phospholipase D (PLD) signaling in the amygdala, a key brain area for the formation and expression of associative memories downstream to serotonin (5-hydroxytryptamine, 5-HT) 2C receptors (5-HT2CRs). We propose to investigate the requirement of PLD and 5-HT2CR function for the expression of cocaine induced conditioned hyperactivity behavior using pharmacological intervention and to determine the effect of modulating PLD activity specifically in the amygdala and study its effect on 5-HT2CR mediated suppression of conditioned hyperactivity. Such amygdala specific experimental investigation of cocaine-cue associated neuroadaptations in long-term memory mechanism act two-fold by advancing the basic understanding of the signaling mechanism associated with drug-environment conditioned associations and performing preliminary investigations of therapeutic potential in preclinical models directed towards reducing the risk of relapse.