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

多巴胺神经元在VTA中起着非常重要的生理作用以及成瘾作用。 行为。本提案的主要目的是阐明塑性在以下方面的关系 腹侧被盖区(VTA)的兴奋性突触与成瘾行为 可卡因的致敏和自我给药。在本供资期间(2002年4月1日至2月 ，我们收集了可能解释NMDAR导致的事件序列的证据 急性应用可卡因引起的VTA对VTA神经元长时程增强的激活 结果是体内接触可卡因的结果。此外，我们的初步数据表明，从长期来看 VTA兴奋性突触传递的改变不仅仅是被动可卡因引起的 给药(如体内注射可卡因)，但操作性行为，如可卡因自身给药。 特定目标1将检验这一假设，即体内可卡因诱导的增强涉及以下直接作用 NMDARs、D5受体和cAMP/PKA依赖通路介导的VTA内可卡因。特定的 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 和行为敏感化。最后，特定目标3将描述长期突触变化是否在 VTA内的谷氨酸能突触是在操作者被迫禁欲或消亡时产生的 对食物或可卡因有反应。综上所述，这些实验的结果可能会帮助我们 了解VTA内谷氨酸能突触可塑性在介导可卡因依赖中的作用 行为。

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.