Mechanisms of Cocaine Induced Long-term Potentiation

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期可塑性 在体内暴露一次后。VTA被认为在 药物相关行为的启动，如行为敏感化，但 启动这种行为的细胞机制 这些现象仍然很模糊。我们的初步数据显示， 注射可卡因可产生长时程增强(LTP) AMPA受体介导的VTA突触后电流。此外，当 他们显示，对小鼠进行了第二次可卡因注射 上下文相关的行为敏感化。此外，可卡因诱导的LTP 和上下文相关的行为敏感化被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 涉及AMPA受体数量、功能或两者的改变。第二，我们将 进行VTA体内注射，以了解VTA内注射 足够的可卡因诱导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VTA中的哪些受体 参与产生可卡因介导的长时程增强。第四，我们 将确定这种可卡因依赖的LTP是否也发生在第三代 细胞，一组功能尚不清楚的VTA神经元。我们的长期合作 目标是了解细胞和分子事件的完整序列 可卡因通过这种方式在VTA的AMPA受体和 随后启动行为敏感化。

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.