Ventral tegmental area dopamine in cocaine self administration and relapse

描述（由申请人提供）：多巴胺（DA）信号传导因其在奖励相关过程中的作用而受到相当大的关注，包括寻求药物的动机和响应药物相关线索的复发（1-4）。腹侧被盖区（VTA）中的DA细胞或诸如延髓核等区域中的DA末梢的破坏了药物自我给药（5-6），并且DA受体拮抗剂的给药减弱了药物相关刺激促进恢复的能力（7）。在人类成瘾者中，响应于药物相关刺激的纹状体DA释放与药物渴望增加和未来复发相关（8，9）。虽然DA通常与药物服用和复发有关，但DA系统迄今尚未被操纵，其时间精度和细胞类型特异性需要隔离它们在这些行为的特定方面的作用。光遗传学工具已被应用于靶向转基因小鼠中的DA神经元，表明DA信号传导支持行为条件反射并促进对食物的工具性反应（20-21）。最近，开发了Th：Cre转基因大鼠系，其允许在优化用于大鼠的更复杂的行为范例中用光遗传学方法选择性靶向DA神经元（22-23）。在这个建议中，我将利用Th：Cre大鼠，结合体内光遗传学和电生理学与复杂的行为分析，探索DA信号传导的因果关系的贡献，以不同方面的工具可卡因的摄入量和复发巴甫洛夫可卡因刺激。首先，在目的1中，我建议测试腹侧被盖区DA神经元激活的充分性，以调节可卡因自我管理和可卡因线索诱导的恢复。第二，在目标2中，我建议测试DA信号的必要性，通过抑制腹侧被盖区DA神经元，可卡因的摄入和恢复。此外，腹侧被盖区不仅包含DA神经元，而且还包含相当大一部分非DA神经元的异质混合物，这些神经元有助于动机处理（11-19），但关于腹侧被盖区中不同的神经元群体如何编码药物相关行为知之甚少。因此，在目的3中，我提出在自我施用和恢复期间表征光遗传学鉴定的腹侧被盖区DA神经元（16）的放电模式。

DESCRIPTION (provided by applicant): Dopamine (DA) signaling has received considerable attention for its role in reward-related processes, including the motivation to seek drugs and relapse in response to drug-associated cues (1-4). Destruction of DA cells in the ventral tegmental area (VTA), or DA terminals in regions such as the nucleus accumbens, disrupts drug self-administration (5-6) and administration of DA receptor antagonists attenuates the ability of drug-associated stimuli to promote reinstatement (7). In human addicts, striatal DA release in response to drug-associated stimuli is associated with increased drug craving and future relapse (8,9). Though DA has been generally implicated in drug taking and relapse, DA systems have thus far not been manipulated with the temporal precision and cell-type specificity required to isolate their role in specific aspects of those behaviors. Optogenetic tools have been applied to target DA neurons in transgenic mice, demonstrating that DA signaling supports behavioral conditioning and facilitates instrumental responding for food (20-21). More recently, a Th:Cre transgenic ratline was developed that allows for the selective targeting of DA neurons with optogenetic methods (22-23) in more complex behavioral paradigms optimized for use in rats. In this proposal, I will utilize Th:Cre rats, incorporating in vivo optogenetics and electrophysiology in combination with sophisticated behavioral analyses, to probe the causal contribution of DA signaling to different aspects of instrumental cocaine intake and relapse in response to Pavlovian cocaine stimuli. First, in Aim 1 I propose to test the sufficiency of VTA DA neuron activation to modulate cocaine self-administration and cocaine cue-induced reinstatement. Second, in Aim 2 I propose to test the necessity of DA signaling, via inhibition of VTA DA neurons, for cocaine intake and reinstatement. Additionally, the VTA contains a heterogeneous mixture of not only DA neurons, but also a substantial fraction of non-DA neurons that contribute to motivational processing (11-19), but little is known about how different populations of neurons in the VTA encode drug-related behaviors. Thus, in Aim 3 I propose to characterize the firing patterns optogenetically-identified VTA DA neurons (16) during self-administration and reinstatement.