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: 7353753
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 7.09万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7353753
• 关键词: 6-Cyano-7-nitroquinoxaline-2,3-dione; Abbreviations; Agonist; Amygdaloid structure; Animal Model; Autoreceptors; Basal Ganglia; Behavior; Bilateral; Cell Nucleus; Cocaine; Cocaine Dependence; Cocaine Users; Computer information processing; Condition; Contralateral; Coupled; Critical Pathways; Cues; Data; Development; Dorsal; Dose; Elements; Environment; Excitatory Amino Acid Antagonists; Exposure to; Family; Figs - dietary; Food; Ganglia; Glutamate Receptor; Glutamates; Goals; Hippocampal Formation; Hippocampus (Brain); Impairment; Incentives; Infusion procedures; Ipsilateral; Lateral; Locomotion; Maps; Measures; Medial; Mediating; Memory; Metabotropic Glutamate Receptors; Methods; Modeling; Motivation; Myxoid cyst; Neurobiology; Nucleus Accumbens; Output; Pharmaceutical Preparations; Play; Prefrontal Cortex; Process; Rattus; Relapse; Relative (related person); Research Personnel; Rewards; Role; Specificity; Statistically Significant; Stimulus; Structure; System; Techniques; Testing; Tetrodotoxin; Ventral Tegmental Area; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; attenuation; base; classical conditioning; cognitive function; craving; disorder later incidence prevention; drug relapse; entorhinal cortex; frontal lobe; metabotropic glutamate receptor type 1; neural circuit; neuroadaptation; novel; paired stimuli; programs; receptor; relating to nervous system

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.

暴露于与可卡因相关的环境会引起对可卡因的渴望和/或增加可卡因复发的倾向 用户。持续且反复出现的环境引发的可卡因动机可能是由可卡因的可塑性引起的 联想学习、记忆、动机和执行认知功能，涉及 海马结构、杏仁核、伏隔核和额叶皮质都存在这种现象。然而，神经 由于动物模型的稀缺，环境引起的药物复发的基础在很大程度上尚未被表征 可用于评估预测药物可用性的环境刺激的激励效果，而不是 条件刺激的动机效应与可卡因输注明确配对。使用新的动物模型 我们最近证明，可卡因的寻求是通过暴露于可预测药物可用性的环境而引起的 背侧海马（DH）、基底外侧杏仁核（BLA）、背内侧前额叶皮质的功能完整性 （dmPFC）和伏隔核（NACc）对于恢复可卡因寻求的情境是必要的。采取 系统神经生物学方法，拟议的项目通过进一步扩展了这一关键途径的映射 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，在使用河豚毒素恢复可卡因和食物寻找的过程中- 诱导可逆性神经失活方法。该项目还将利用类似的技术进一步研究 NACc 和伏隔核壳参与可卡因和食物寻求的情境恢复，因为 假设前一个结构是朝向基底神经节的复发电路的输入结构（目标 1）。 然后，可逆的不对称失活（即断开）将用于检验以下假设： 上下文复发电路，顺序信息处理发生在 DH 和 dmPFC 之间以及 BLA 和 dmPFC 通过并行循环，然后信息依次由 dmPFC 和 NACc 处理（目的 2）。最后，该项目将测试 AMPA 和代谢型谷氨酸 (mGLU) 受体在 复发回路在情境恢复和可卡因诱导的这些受体的适应中发挥着关键作用 系统有助于寻找可卡因。为此，该项目将检查局部注射的剂量依赖性影响 选择性 AMPA、第 1 组 mGLU 和第 2 组 mGLU 受体拮抗剂和/或激动剂用于背景恢复 可卡因和食物寻求（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。得到的数据有 可能为开发针对线索诱导的药物复发的新疗法提供依据。