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

腹侧被盖区的多巴胺神经元在多种生理以及成瘾中起着非常重要的作用 行为。本提案的主要目标是阐明塑性与 腹侧被盖区（VTA）的兴奋性突触和成瘾行为， 致敏和自我施用可卡因。在目前的资助期间（2002年4月1日至2003年2月）， 2006年），我们已经收集了可能解释NMDAR导致的事件序列的证据 急性可卡因应用产生的腹侧被盖区激活，到腹侧被盖区神经元的长时程增强， 结果是体内可卡因暴露的结果。此外，我们的初步数据表明，长期 腹侧被盖区兴奋性突触传递的改变不仅是由被动可卡因引起的， 例如，体内可卡因注射（e.g.in vivo cocaine injections），但操作性行为如可卡因自我给药。 具体目标1将检验体内可卡因诱导的增强作用涉及以下直接作用的假设： 通过NMDAR、D5受体和cAMP/PKA依赖性途径介导的VTA中的可卡因。具体 目的2将测试蛋白质合成在介导腹侧被盖区突触长时程可塑性中的作用和时程 和行为敏感化。最后，具体目标3将描述是否长期突触变化， 腹侧被盖区的突触是在强迫禁欲或操作性兴奋消失时产生的。 对食物或可卡因有反应综合起来，这些实验的结果可能会帮助我们 了解VTA中突触的可塑性在介导可卡因依赖性中的作用 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.