Relapse and 5-HT2CR-PLD signaling in rat amygdala

描述（由申请人提供）：在对与吸毒有关的线索（视觉、听觉、触觉）做出反应后，长时间的戒断可能会导致可卡因的复发。反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，在关键的大脑区域诱发长期变化（神经适应）。与可卡因有关的奖励特性和内感受与环境线索有关。这种关联在临床上很重要，因为强烈的药物渴望导致成瘾者极易复发，这主要发生在对这种环境线索的反应中。然而，我们对药物依赖性习得关联的分子机制仍然知之甚少。在本研究中，我们将验证一种假设，即对先前的可卡因配对环境的条件行为反应的表达需要杏仁核中的磷脂酶D （PLD）信号，杏仁核是形成和表达下游5-羟色胺（5-羟色胺，5-羟色胺）2C受体（5-HT2CRs）联想记忆的关键脑区。我们拟通过药物干预研究PLD和5-HT2CR功能对可卡因诱导的条条性多动行为表达的要求，确定特异性调节杏仁核PLD活性的作用，并研究其对5-HT2CR介导的条条性多动的抑制作用。这种针对长期记忆机制中可卡因线索相关神经适应性的杏仁核特异性实验研究，通过促进对与药物-环境条件关联相关的信号机制的基本理解，以及在临床前模型中针对降低复发风险的治疗潜力进行初步研究，起到了双重作用。

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.