Synaptic Plasticity in Animal Models of Addiction

描述（由申请人提供）：成瘾是一种慢性复发性疾病。尽管长期戒断，成瘾者可能会在再次接触毒品、暗示或压力时产生强烈的渴望。强烈的渴望是如何重新出现的，神经生物学上的触发因素是什么？伏隔核（NAc）是哺乳动物大脑中成瘾药物的关键靶点。动物模型提示NAc与药物寻求恢复的持久脆弱性有关。虽然恢复涉及NAc ampa型谷氨酸受体（AMPARs）的可塑性，但这种可塑性的身份尚不清楚。结合啮齿动物恢复模型和NAc离体全细胞记录，我们确定了一个假定的复发神经底物。在可卡因戒断期间，体内或体外的可卡因启动物诱导AMPAR长期抑制（“再暴露有限”），表明戒断期间NAc AMPAR对环境刺激的反应可塑性是高度动态的。我们假设再暴露为恢复提供了一个突触通道。为了验证这一点，我们将直接测量和操纵NAc AMPAR在药物、线索和应力引发的恢复和孵育模型中的可塑性。此外，“碟中启动”为我们研究修复相关可塑性的分子机制提供了一个可操作的模型系统。我们假设在戒断期间“支持”NAc AMPAR功能可能是对抗复发的有用工具。

DESCRIPTION (provided by applicant): Addiction is a chronic relapsing disorder. Despite extended abstinence, addicts may experience intense craving in response to drug re-exposure, cues or stress. How do strong cravings re-emerge and what are the neurobiological triggers? Nucleus accumbens (NAc) is a key target of addictive drugs in the mammalian brain. Animal models implicate NAc in enduring vulnerability to reinstatement of drug seeking. Although reinstatement involves plasticity in NAc AMPA-type glutamate receptors (AMPARs), the identity of this plasticity is unclear. Combining rodent reinstatement models with NAc whole-cell recordings in an ex vivo preparation, we identified a putative neural substrate for relapse. During cocaine abstinence, a cocaine prime, in vivo or in vitro, induces AMPAR long-term depression ("re-exposure LTD"), indicating that NAc AMPAR plasticity in response to environmental stimuli during abstinence is highly dynamic. We hypothesize that re- exposure LTD provides a synaptic gateway for reinstatement. To test this, we will directly measure and manipulate NAc AMPAR plasticity in drug-, cue- and stress-primed reinstatement and incubation models. In addition, "priming in a dish" gives us a tractable model system to study molecular mechanisms of reinstatement-linked plasticity. We hypothesize that "propping up" NAc AMPAR function during abstinence may be a useful tool in combating relapse.