Synaptic Plasticity in Animal Models of Addiction

描述(申请人提供)：上瘾是一种慢性复吸障碍。尽管长期戒毒，吸毒者在再次接触毒品、线索或压力时可能会经历强烈的渴望。强烈的渴望是如何重新出现的？神经生物学的触发因素是什么？伏隔核(NAC)是哺乳动物大脑中成瘾药物的关键靶点。动物模型表明，NAC在恢复毒品寻求方面具有持久的脆弱性。虽然修复涉及NAc-AMPA型谷氨酸受体(AMPAs)的可塑性，但这种可塑性的身份尚不清楚。结合啮齿动物复原模型和体外制备的NAC全细胞记录，我们确定了复发的可能神经底物。在可卡因戒断期间，在体内或体外，可卡因原剂诱导AMPAR长期抑制(“再暴露有限公司”)，这表明在戒断过程中NAC AMPAR对环境刺激的可塑性是高度动态的。我们假设，Re-Exposure Ltd为恢复提供了一个突触通道。为了测试这一点，我们将在药物、线索和压力启动的恢复和孵化模型中直接测量和操纵NAC AMPAR的可塑性。此外，“盘中启动”为我们提供了一个易于处理的模型系统来研究恢复连锁可塑性的分子机制。我们推测，在禁欲期间“支持”NAC AMPAR功能可能是对抗复发的有用工具。 公共卫生相关性：结合啮齿动物行为模型和先进的细胞电生理技术，我们将调查突触可塑性和药物复发之间的关系。我们已经在伏隔核中发现了一种可能的神经生物学复发触发因素--中脑边缘多巴胺环路的一个区域，该区域在成瘾中起关键作用。我们希望我们的研究能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.