Ventral tegmental area dopamine in cocaine self administration and relapse

描述（由申请人提供）：多巴胺（DA）信号因其在奖励相关过程中的作用而受到相当多的关注，包括寻求药物的动机和药物相关线索的复发（1-4）。腹侧被盖区（VTA）的DA细胞或伏隔核等区域的DA终端被破坏，会破坏药物的自我给药（5-6），而DA受体拮抗剂的给药会减弱药物相关刺激促进恢复的能力(7)。在人类成瘾者中，纹状体DA释放对药物相关刺激的反应与药物渴望增加和未来复发有关（8,9）。虽然DA通常与药物服用和复发有关，但到目前为止，DA系统还没有得到时间精度和细胞类型特异性的操纵，以分离出它们在这些行为的特定方面的作用。光遗传学工具已应用于转基因小鼠的目标DA神经元，证明DA信号支持行为条件反射并促进对食物的工具反应（20-21）。最近，一种Th:Cre转基因鼠系被开发出来，它允许在更复杂的行为模式下，用光遗传学方法选择性地靶向DA神经元（22-23）。在本提案中，我将利用Th:Cre大鼠，结合体内光遗传学和电生理学，结合复杂的行为分析，探讨DA信号在巴甫洛夫可卡因刺激下的可卡因摄入和复发的不同方面的因果贡献。首先，在目的1中，我提议测试VTA DA神经元激活调节可卡因自我给药和可卡因线索诱导的恢复的充分性。其次，在目标2中，我建议通过抑制VTA DA神经元来测试DA信号传导对可卡因摄入和恢复的必要性。此外，VTA不仅包含DA神经元，还包含大量参与动机加工的非DA神经元的异质性混合物（11-19），但对于VTA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Aim 3中，我建议表征光遗传学鉴定的VTA DA神经元在自我给药和恢复期间的放电模式（16）。

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.