Neural Bases of Drug Context-induced Cocaine Seeking

描述（由申请人提供）：暴露于可卡因相关的环境中会使可卡因使用者产生渴望和/或增加复吸的倾向。持续和反复出现的环境引发的可卡因的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，牵连海马结构，杏仁核，杏仁核，额叶皮层在这一现象的参与。然而，背景诱导的药物复吸的神经基础在很大程度上是未知的，部分原因是缺乏动物模型，可用于评估预测药物可用性的环境刺激的激励作用，而不是明确与可卡因输注配对的条件刺激的激励作用。使用一种新的动物模型，其中可卡因寻求引起暴露于预测药物可用性的上下文，我们最近证明，背侧海马（DH），基底外侧杏仁核（BLA），背内侧前额叶皮层（dmPFC）和背内侧核的核心（NACc）的功能完整性是必要的上下文恢复可卡因寻求。以系统神经生物学的方法，拟议的项目扩大了这一关键途径的映射，通过进一步研究海马结构的作用，特别是腹侧海马（VH），下托，和内嗅皮层的参与，在上下文恢复可卡因和食物寻求使用河豚毒素诱导的可逆神经失活方法。使用类似的技术，该项目还将进一步研究NACc和核壳在可卡因和食物寻求的背景恢复中的参与，因为前者的结构被假定为基底神经节复发回路的输入结构（目的1）。可逆不对称失活（即，断开）将用于检验以下假设：在情境复发回路内，顺序信息处理经由平行回路发生在DH和dmPFC之间以及BLA和dmPFC之间，并且信息随后由dmPFC和NACc顺序处理（目标2）。最后，该项目将测试的假设，即AMPA和代谢型谷氨酸（mGLU）受体内的复发电路发挥关键作用的上下文恢复和可卡因诱导的适应，这些受体系统促进可卡因寻求。为此，该项目将检查局部输注的选择性AMPA、第1组mGLU和第2组mGLU受体拮抗剂和/或激动剂对可卡因和食物寻求的背景恢复的剂量依赖性影响（目标3）。总之，本研究的目的是阐明情境可卡因寻求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线索诱导的药物复发的新治疗方法的开发提供理论基础。

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.