Neural Bases of Drug Context-induced Cocaine Seeking

暴露于可卡因相关的环境中会激发对可卡因的渴望和/或增加可卡因复吸的倾向 用户.持续和反复出现的环境引发的可卡因动机可能是由可塑性引起的， 联想学习，记忆，动机和执行认知功能，涉及参与的 海马结构、杏仁核、杏仁核和额叶皮层。然而，神经 背景诱导的药物复吸的基础在很大程度上还没有特征化，部分原因是缺乏动物模型 这可以用来评估环境刺激的激励作用，预测药物的可用性，而不是 条件刺激的动机效应与可卡因注射明确配对。使用新的动物模型， 可卡因寻求是由暴露于预测药物可用性的环境引起的，我们最近已经证明， 背侧海马体（DH）、基底外侧杏仁核（BLA）、背内侧前额叶皮质的功能完整性 （dmPFC）和脑桥核心核（NACc）是可卡因寻求的背景恢复所必需的。采取 系统神经生物学方法，拟议的项目扩大了这一关键途径的映射，进一步 检查海马结构的作用，特别是腹侧海马（VH）的参与， 下托和内嗅皮层，在可卡因和食物寻求使用河豚毒素的背景恢复- 诱导可逆性神经失活方法。利用类似的技术，该项目还将进一步调查 NACc和核壳参与可卡因和食物寻求的背景恢复， 前一种结构被假定为复发回路向基底神经节的输入结构（目的1）。 可逆不对称失活（即，然后将被用来测试假设，在 在情境复发回路中，顺序信息处理发生在DH和dmPFC之间，以及DH和dmPFC之间。 BLA和dmPFC通过并行循环，然后信息由dmPFC和NACc（Aim）顺序处理 2）。最后，该项目将测试假设，AMPA和代谢型谷氨酸（mGLU）受体内的 复发回路在这些受体中背景恢复和可卡因诱导的适应中起关键作用 系统促进可卡因的寻求。为此，该项目将研究局部注入的 选择性AMPA、第1组mGLU和第2组mGLU受体拮抗剂和/或激动剂对环境恢复的影响 可卡因和食物寻求（目标3）。总括而言，拟议项目的目的是阐明 背景可卡因寻求的神经生物学和神经药理学机制。生成的数据具有 可能为线索诱导的药物复发的新治疗方法的开发提供理论基础。

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.