Synaptic plasticity in the VTA after behavioral sensitization & cocaine self-admi

行为敏化后 VTA 的突触可塑性

• 批准号: 7744708
• 负责人: Patricia H. Janak
• 金额: $ 32.37万
• 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 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744708
• 关键词: AMPA Receptors; Abstinence; Acute; Addictive Behavior; Bathing; Behavior; Brain; Chemosensitization; Cocaine; Cyclic AMP Receptors; Data; Development; Event; Excitatory Synapse; Extinction (Psychology); Food; Funding; Glutamates; Goals; Grant; Hour; In Vitro; Injection of therapeutic agent; Laboratories; Learning; Link; Long-Term Potentiation; Mediating; Mediation; Memory; Molecular; Neurons; Pathway interactions; Phase; Physiological; Play; Property; Protein Biosynthesis; Rattus; Role; Self Administration; Self-Administered; Series; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Time; Training; Ventral Tegmental Area; behavioral sensitization; cocaine exposure; dopaminergic neuron; in vivo; receptor function; research study; response

Dopamine neurons in the VTA play a very important role in a variety of physiological as well as addictive behaviors. The main goal of the present proposal is to elucidate the relationship between plasticity at excitatory synapses in the ventral tegmental area (VTA)and addictive behaviors such as behavioral sensitization and self-administration of cocaine. During the current funding period (April1st, 2002- February 2006), we have collected evidence that might explain the sequence of events leading from NMDAR activation in the VTA produced by acute cocaine application, to long-term potentiation of VTA neurons that results as a consequence of in vivo cocaine exposure. Further, our preliminary data suggest that long-term changes of excitatory synaptic transmission in the VTA are not only produced by passive cocaine administration (e.g.in vivo cocaine injections), but operant behaviors such as cocaine self-administration. Specific aim 1 will test the hypothesis that in vivo cocaine-induced potentiation involves a direct action of cocaine in the VTA mediated by NMDARs, D5 receptors and the cAMP/PKA-dependent pathway. Specific aim 2 will test the role and time-course of protein synthesis in mediating long-term plasticity at VTA synapses and behavioral sensitization. Finally, specific aim 3 will characterize whether long-term synaptic changes at glutamatergic synapses in the VTA are produced during forced abstinence or extinction of operant responding from either food or cocaine. Taken together, the results from these experiments will likely help us understand the role of plasticity at glutamatergic synapses in the VTA in mediating cocaine-dependent behaviors.

VTA中的多巴胺神经元在多种生理以及成瘾中发挥着非常重要的作用 行为。本提案的主要目标是阐明可塑性之间的关系 腹侧被盖区（VTA）的兴奋性突触和成瘾行为，例如行为 可卡因的致敏和自我给药。在本次资助期间（2002年4月1日-2月 2006），我们收集了可能解释 NMDAR 导致的事件顺序的证据 急性可卡因应用产生的 VTA 激活，对 VTA 神经元的长期增强 体内可卡因暴露的结果。此外，我们的初步数据表明，长期 VTA 兴奋性突触传递的变化不仅是由被动可卡因引起的 给药（例如体内可卡因注射），但操作行为例如可卡因自我给药。 具体目标 1 将检验以下假设：体内可卡因诱导的增强涉及以下物质的直接作用： VTA 中的可卡因由 NMDAR、D5 受体和 cAMP/PKA 依赖性途径介导。具体的 目标 2 将测试蛋白质合成在调节 VTA 突触长期可塑性中的作用和时间进程 和行为敏感性。最后，具体目标 3 将描述长期突触变化是否在 VTA 中的谷氨酸突触是在强制禁欲或操作性消失期间产生的 来自食物或可卡因的反应。总而言之，这些实验的结果可能会帮助我们 了解 VTA 谷氨酸突触可塑性在介导可卡因依赖性中的作用 行为。