Accumbens shell mu-opioid signaling in alcohol self-administration and relapse

描述(由申请人提供)：大量证据表明内源性阿片类药物在饮酒和强化中的重要性(1)。伏隔核的内侧壳(NAC)已经成为这些效应的重要神经底物，并可能调节问题酒精的使用(2-9)。重要的是，向啮齿动物NAC中注入Mu阿片受体激动剂DAMGO会增加酒精摄入量，但这种影响的行为和神经机制仍不清楚。内侧NAc壳是前额叶皮质对下丘脑和腹侧苍白球的影响的关键继电器，形成一个可能替代通常致力于饱腹感的机制的“消退回路”，而该回路的调制可能是阿片类药物诱导的酒精消耗和复发的关键机制(11-12)。从下缘皮质到内侧NAc壳的谷氨酸能输入被认为是在灭绝和恢复期间抑制药物和酒精寻求(13-14)，可能是通过从NAc到腹侧苍白球和外侧下丘脑的抑制性投射(11，15)。这些实验将系统地测试NAC DAMGO诱发饮酒的心理和神经机制，特别是NAC壳DAMGO对这一消退回路的影响。本提案目标1中的实验将测试NAC外壳DAMGO在酒精自我给药和线索诱导的酒精寻求复吸中的具体作用，以确定NAC mu阿片信号(即适口性、动机或强化)增强了酒精奖赏的哪些方面。了解NAC外壳类阿片信号如何影响来自下缘皮质的自上而下的输入是至关重要的，而下缘皮质通常可能抑制酒精寻求和复发。研究计划的目标2将测试选择性激活下缘传入NAC是否可以在酒精自我给药和复发期间抑制酒精消费和复发，以及NAC壳DAMGO是否可以阻断这些影响。同样重要的是要了解NAC类阿片引起的酒精寻求变化是如何在消退回路的下游结构中编码的，包括腹侧苍白球和外侧下丘脑，这可能编码酒精奖励的不同方面。Aim 3中的实验将测试下丘脑外侧或腹侧苍白球的神经活动是否编码了酒精寻求、消费或重新饮酒，或者在NAC外壳DAMGO后这些过程中的任何一种增强。

DESCRIPTION (provided by applicant): A large body of evidence points to the importance of endogenous opioids in alcohol drinking and reinforcement (1). The medial shell of nucleus accumbens (NAc) has emerged as an important neural substrate for these effects and may mediate problem alcohol use (2-9). Importantly, infusion of the mu-opioid receptor agonist, DAMGO, into rodent NAc potentiates alcohol consumption (10), yet the behavioral and neurological mechanisms of this effect remain unknown. Medial NAc shell is a critical relay for prefrontal cortical influences on both hypothalamus and ventral pallidum, forming an "extinction circuit" which may co -opt mechanisms normally devoted to satiety, and modulation of this circuit may serve as a critical mechanism of opioid-induced alcohol consumption and relapse (11-12). Glutamatergic inputs from infralimbic cortex to medial NAc shell are posited to suppress drug and alcohol seeking following extinction and during reinstatement (13- 14), potentially via inhibitory projections from NAc to ventral pallidum and lateral hypothalamus (11, 15). The proposed experiments will systemically test the psychological and neural mechanisms of NAc DAMGO- induced alcohol consumption, and in particular the effects of NAc shell DAMGO on this extinction circuit. The experiments in Aim 1 of this proposal will test the specific effects o NAc shell DAMGO in alcohol self - administration and cue-induced relapse to alcohol seeking, to determine what aspects of alcohol reward are enhanced by NAc mu-opioid signaling (i.e. palatability, motivation, or reinforcement). It is critical to understand how NAc shell mu-opioid signaling affects top-down inputs from infralimbic cortex that may normally suppress alcohol seeking and relapse. Aim 2 of the research plan will test whether selective activation of infralimbic inputs to NAc can suppress alcohol consumption and relapse, and whether NAc shell DAMGO blocks these effects, during alcohol self-administration and relapse. It is also vital to understand how NAc mu-opioid induced changes in alcohol seeking are encoded in downstream structures of the extinction circuit, including ventral pallidum and lateral hypothalamus, which may encode different aspects of alcohol reward. The experiments in Aim 3 will test whether neural activity in lateral hypothalamus or ventral pallidum encodes alcohol seeking, consumption, or relapse to alcohol seeking, or enhancements in any of these processes following NAc shell DAMGO.