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。 公共卫生相关性：使用啮齿动物行为模型和先进的细胞电生理技术相结合，我们将研究突触可塑性和药物复发之间的关系。我们已经确定了一个假定的神经生物学复发触发核中脑边缘多巴胺回路的一个地区，是成瘾的关键。我们希望我们的研究为复发预防和治疗提供新的策略。

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. PUBLIC HEALTH RELEVANCE: Using a combination of rodent behavioral models and advanced cellular electrophysiological techniques, we will investigate the relationship between synaptic plasticity and drug relapse. We have identified a putative neurobiological relapse trigger in the nucleus accumbens-a region of the mesolimbic dopamine circuit that is critical in addiction. We expect our studies to inform new strategies for relapse prevention and treatment.