Neural Bases of Drug Context-induced Cocaine Seeking

药物环境诱发的可卡因寻求的神经基础

• 批准号: 7083313
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 7万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-05 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7083313
• 关键词: AMPA receptors; amygdala; behavior test; behavioral /social science research tag; biological models; cocaine; craving; cues; dosage; entorhinal cortex; food; glutamate receptor; hippocampus; laboratory rat; male; motivation; neural information processing; neuroanatomy; neurobiology; neuropharmacology; nucleus accumbens; prefrontal lobe /cortex; relapse /recurrence; substance abuse related behavior; substance abuse related disorder

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.

描述（由申请人提供）：暴露于可卡因相关环境会引起可卡因使用者的渴望和/或复吸倾向增加。持续且反复出现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，这表明海马结构、杏仁核、伏核和额叶皮层参与了这种现象。然而，环境诱发的药物复吸的神经基础在很大程度上尚未被表征，部分原因是缺乏可用于评估预测药物可用性的环境刺激的动机效应的动物模型，而不是与可卡因输注明确配对的条件刺激的动机效应。使用一种新的动物模型，其中可卡因寻求是通过暴露于可预测药物可用性的环境中而引发的，我们最近证明了背侧海马（DH）、基底外侧杏仁核（BLA）、背内侧前额叶皮层（dmPFC）和伏隔核（NACc）的功能完整性对于可卡因的环境恢复是必要的 寻求。该项目采用系统神经生物学方法，通过进一步检查海马结构的作用，特别是腹侧海马（VH）、下托和内嗅皮层的参与，使用河豚毒素诱导的可逆神经失活方法在可卡因和食物寻找的情境恢复中扩展了这一关键通路的映射。使用类似的技术，该项目还将进一步研究 NACc 和伏隔核壳在可卡因和食物寻求的情境恢复中的参与，因为前一个结构被假定为基底神经节复发回路的输入结构（目标 1）。然后，使用可逆不对称失活（即断开）来测试以下假设：在上下文复发电路内，通过并行循环在 DH 和 dmPFC 之间以及 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，该项目将测试这样的假设：复发回路中的 AMPA 和代谢型谷氨酸 (mGLU) 受体在情境恢复中发挥着关键作用，并且可卡因诱导的这些受体系统的适应促进了可卡因的寻求。为此，该项目将检查局部注射选择性 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食物寻求的恢复的剂量依赖性影响（目标 3）。总之，拟议项目的目标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开发针对线索诱导的药物复发的新疗法提供依据。