Neural Bases of Drug Context-induced Cocaine Seeking

描述(由申请人提供)：暴露在与可卡因有关的环境中会引起可卡因使用者的渴望和/或复发倾向的增加。持续和反复发生的环境触发的可卡因动机可能是由联想学习、记忆、动机和执行认知功能的可塑性引起的，涉及到海马结构、杏仁核、伏隔核和额叶皮质的参与。然而，环境诱导的药物复发的神经基础在很大程度上还没有确定，部分原因是缺乏可以用来评估预测药物可用性的环境刺激的动机效应的动物模型，而不是与可卡因注射明确配对的条件刺激的动机效应。使用一种新的动物模型，在该模型中，通过暴露于预测药物可获得性的背景，我们最近证明了背侧海马区(DH)、基底外侧杏仁核(BLA)、背内侧前额叶皮质(DmPFC)和伏隔核核心(NACC)的功能完整性对于背景恢复可卡因寻找是必要的。采用系统神经生物学的方法，通过进一步研究海马结构的作用，特别是腹侧海马(VH)、下丘脑和内嗅觉皮质的参与，利用河豚毒素诱导的可逆神经失活方法，在上下文中恢复可卡因和寻找食物，该项目扩展了这一关键途径的图谱。使用类似的技术，该项目还将进一步研究NACC和伏隔核外壳在上下文恢复可卡因和寻找食物中的参与，因为前者被假设为向基底节的复发回路的输入结构(目标1)。然后将使用可逆的不对称失活(即断开)来测试这样的假设，即在上下文复发电路内，经由并行环路在DH和dmPFC之间以及在BLA和dmPFC之间发生顺序信息处理，然后由dmPFC和NACC顺序处理信息(目标2)。最后，该项目将测试假说，即复发回路中的AMPA和代谢性谷氨酸(MGLU)受体在上下文恢复中发挥关键作用，以及可卡因在这些受体系统中诱导的适应促进可卡因寻求。为此，该项目将研究局部注射选择性AMPA、第1组mGLU和第2组mGLU受体拮抗剂和/或激动剂对可卡因和寻找食物的上下文恢复的剂量依赖效应(目标3)。总之，拟议项目的目标是阐明与可卡因相关的神经生物学和神经药理学机制。由此产生的数据有可能为开发线索诱导的药物复发的新治疗方法提供理论基础。

DESCRIPTION (provided by applicant): Exposure to a cocaine-associated environment elicits craving and/or an increase in propensity for relapse in cocaine users. Persistent and reoccurring environmentally triggered motivation for cocaine is likely elicited by plasticity in associative learning, memory, motivation, and executive cognitive function, implicating the involvement of the hippocampal formation, amygdala, nucleus accumbens, and frontal cortex in this phenomenon. However, the neural bases of context-induced drug relapse have been largely uncharacterized in part due to the scarcity of animal models that can be used to assess the motivational effects of environmental stimuli predictive of drug availability, as opposed to the motivational effects of conditioned stimuli paired explicitly with cocaine infusions. Using a new animal model in which cocaine seeking is elicited by exposure to a context predictive of drug availability, we have recently demonstrated that the functional integrity of the dorsal hippocampus (DH), basolateral amygdala (BLA), dorsomedial prefrontal cortex (dmPFC) and nucleus accumbens core (NACc) is necessary for contextual reinstatement of cocaine seeking. Taking a systems neurobiological approach, the proposed project expands the mapping of this critical pathway by further examining the role of the hippocampal formation, specifically the involvement of the ventral hippocampus (VH), subiculum, and entorhinal cortex, in contextual reinstatement of cocaine and food seeking using the tetrodotoxin-induced reversible neural inactivation method. Using similar techniques, the project will also further investigate the involvement of the NACc and nucleus accumbens shell in contextual reinstatement of cocaine and food seeking, as the former structure is postulated to be the input structure of the relapse circuitry toward the basal ganglia (Aim 1). Reversible asymmetrical inactivation (i.e., disconnection) will then be used to test the hypothesis that, within the contextual relapse circuitry, sequential information processing occurs between the DH and dmPFC as well as between the BLA and dmPFC via parallel loops, and information is then sequentially processed by the dmPFC and NACc (Aim 2). Lastly, the project will test the hypotheses that AMPA and metabotropic glutamate (mGLU) receptors within the relapse circuitry play a critical role in contextual reinstatement and that cocaine-induced adaptations in these receptor systems facilitate cocaine seeking. To this end, the project will examine dose-dependent effects of locally infused selective AMPA, group 1 mGLU, and group 2 mGLU receptor antagonists and/or agonists on contextual reinstatement of cocaine and food seeking (Aim 3). In summary, the objective of the proposed project is to elucidate the neurobiological and neuropharmacological mechanisms of contextual cocaine seeking. The resulting data have the potential to provide a rationale for the development of novel treatments for cue-induced drug relapse.