Mechanisms of Cocaine Induced Long-term Potentiation

可卡因诱导长时程增强的机制

• 批准号: 6878935
• 负责人: ANTONELLO BONCI
• 金额: $ 24.11万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878935
• 关键词: AMPA receptors; behavioral habituation /sensitization; brain electrical activity; cell cell interaction; cell population study; chemical structure function; cocaine; immunocytochemistry; intermolecular interaction; laboratory rat; long term potentiation; neural plasticity; neural transmission; neurogenetics; neurons; neuropharmacology; neuroregulation; phosphorylation; receptor coupling; receptor expression; second messengers; synapses; tegmentum; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): The goal of the present proposal is to understand the cellular and synaptic events through which cocaine induces long-term plasticity at excitatory synapses in the ventral tegmental area (VTA) after a single in vivo exposure. The VTA considered to play a central role in the initiation of drug-related behaviors such as behavioral sensitization, but the cellular mechanisms that underlie the initiation of such behavioral phenomena are still obscure. Our preliminary data suggest that a single injection of cocaine produces a long-term potentiation (LTP) of AMPA-receptor-mediated post-synaptic currents in the VTA. Furthermore, when mice were challenged with a second injection of cocaine, they displayed context-dependent behavioral sensitization. Further, both cocaine-induced LTP and context-dependent behavioral sensitization are blocked by the NMDA receptor antagonist MK-801. Our first goal is to determine whether the expression of cocaine-induced LTP involves a change in AMPA receptor number, function, or both. Second, we will perform intra-VTA in vivo injections to understand whether intra-VTA injections of cocaine are sufficient for cocaine to induce LTP, and to define the receptors and second messengers involved in producing the cocaine-induced LTP. Third, we will use an in vitro model to study which receptors in the VTA are involved in producing the cocaine-mediated long-term potentiation. Fourth, we will determine whether such cocaine dependent LTP also occurs in tertiary cells, a group of VTA neurons whose function is still unknown. Our long-term goal is to understand the complete sequence of cellular and molecular events through which cocaine produces LTP at AMPA receptors in the VTA and the subsequent initiation of behavioral sensitization.

描述（由申请人提供）：本提案的目标是 了解可卡因诱导的细胞和突触事件 腹侧被盖区兴奋性突触的长时程可塑性 在单次体内暴露后。VTA被认为在以下方面发挥核心作用： 药物相关行为的开始，如行为敏感化，但 这种行为启动的细胞机制 现象仍然模糊。我们的初步数据表明， 注射可卡因产生长时程增强（LTP）， 腹侧被盖区AMPA受体介导的突触后电流。此外，当 第二次注射可卡因后， 情境依赖行为敏感化此外，可卡因诱导的LTP 和情境依赖性行为敏感化被NMDA受体阻断 拮抗剂MK-801。 我们的第一个目标是确定可卡因诱导的LTP的表达是否 涉及AMPA受体数量、功能或两者的变化。二是 进行VTA内体内注射，以了解VTA内注射是否 可卡因足以诱导LTP，并定义 受体和第二信使参与产生可卡因诱导的LTP。 第三，我们将使用体外模型来研究腹侧被盖区中的哪些受体是 参与产生可卡因介导的长时程增强。四是 将确定这种可卡因依赖性LTP是否也发生在第三级 细胞，一组腹侧被盖区神经元，其功能仍然未知。我们的长期 目标是了解细胞和分子事件的完整顺序 可卡因通过腹侧被盖区和腹侧被盖区的AMPA受体产生LTP， 随后引发行为敏感化。