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

描述(申请人提供)：VTA中的多巴胺神经元在各种生理和成瘾行为中发挥着非常重要的作用。本研究的主要目的是阐明腹侧被盖区兴奋性突触的可塑性与行为敏感化和自身给药等成瘾行为之间的关系。在目前的资助期间(2002年4月1日-2006年2月)，我们收集了一些证据，可以解释从急性应用可卡因产生的VTA中NMDAR激活到体内可卡因暴露导致VTA神经元的长期增强的一系列事件。此外，我们的初步数据表明，VTA兴奋性突触传递的长期变化不仅由被动的可卡因注射(例如体内注射可卡因)产生，而且还包括可卡因自身给药等可操作性行为。具体目标1将验证这样的假设，即在体内可卡因诱导的增强涉及可卡因通过NMDARs、D5受体和cAMP/PKA依赖途径介导的VTA的直接作用。特定目标2将测试蛋白质合成在调节VTA突触的长期可塑性和行为敏化中的作用和时间进程。最后，特殊目标3将描述VTA内谷氨酸能突触的长期突触变化是在强制戒断或消除对食物或可卡因的反应时产生的。综上所述，这些实验的结果可能有助于我们理解VTA中谷氨酸能突触的可塑性在介导可卡因依赖行为中的作用。

DESCRIPTION (provided by applicant): 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.