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。尽管长期禁欲，成瘾者可能会经历强烈的渴望，以回应药物重新暴露，线索或压力。强烈的渴望是如何重新出现的，神经生物学触发因素是什么？延髓核（NAc）是哺乳动物大脑中成瘾药物的关键靶点。动物模型暗示NAc在持久的脆弱性恢复药物寻求。虽然恢复涉及NAc AMPA型谷氨酸受体（AMPAR）的可塑性，但这种可塑性的身份尚不清楚。结合啮齿类动物复发模型与NAc全细胞记录在离体制剂，我们确定了一个假定的神经基板复发。在可卡因戒断期间，体内或体外的可卡因引发诱导AMPAR长期抑制（“再暴露LTD”），表明戒断期间响应于环境刺激的NAc AMPAR可塑性是高度动态的。我们假设再暴露LTD为恢复提供了一个突触通道.为了测试这一点，我们将直接测量和操纵NAc AMPAR可塑性药物，线索和压力引发的恢复和孵化模型。此外，“引发在一个菜”给了我们一个易于处理的模型系统，研究分子机制的恢复连接的可塑性。我们推测，在禁欲期间“支撑”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.