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: 7208307
• 负责人: ANTONELLO BONCI
• 金额: $ 31.8万
• 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/7208307
• 关键词: Abstinence; Acute; Addictive Behavior; Bathing; Behavior; Brain; Chemosensitization; Chromosome Pairing; 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; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; behavioral sensitization; day; dopaminergic neuron; in vivo; receptor function; research study; response

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.

描述（由申请人提供）：腹侧被盖区的多巴胺神经元在多种生理和成瘾行为中起着非常重要的作用。本研究的主要目的是阐明腹侧被盖区（VTA）兴奋性突触的可塑性与成瘾行为（如行为敏化和可卡因自我给药）之间的关系。在目前的资助期间（2002年4月1日至2006年2月），我们收集的证据，可能会解释的事件导致从急性可卡因应用产生的腹侧被盖区的NMDAR激活的序列，长时程增强的腹侧被盖区神经元的结果，在体内可卡因暴露。此外，我们的初步数据表明，在腹侧被盖区的兴奋性突触传递的长期变化不仅产生被动可卡因管理（如体内可卡因注射），但操作性行为，如可卡因自我管理。具体目标1将检验以下假设：体内可卡因诱导的增强作用涉及可卡因在由NMDAR、D5受体和cAMP/PKA依赖性途径介导的VTA中的直接作用。具体目标2将测试蛋白质合成在介导腹侧被盖区突触的长期可塑性和行为敏化中的作用和时间过程。最后，具体目标3将表征腹侧被盖区中的突触能突触的长期突触变化是否是在食物或可卡因的操作性反应的强制戒断或消退期间产生的。总之，这些实验的结果将可能帮助我们理解VTA中的突触可塑性在介导可卡因依赖行为中的作用。