Ventral tegmental area dopamine in cocaine self administration and relapse

描述(由申请人提供)：多巴胺(DA)信号因其在奖赏相关过程中的作用而受到相当大的关注，包括对与药物相关的线索做出反应时寻求药物和复发的动机(1-4)。破坏腹侧被盖区(VTA)的DA细胞，或伏隔核等区域的DA终末，会扰乱药物的自我给药(5-6)，给药DA受体拮抗剂会减弱药物相关刺激促进恢复的能力(7)。在人类吸毒者中，纹状体DA对药物相关刺激的反应与药物渴求增加和未来复发有关(8，9)。虽然DA通常与吸毒和复发有关，但迄今为止，DA系统还没有被以时间精确度和细胞类型特异性来操纵，以分离它们在这些行为的特定方面所起的作用。光遗传学工具已被应用于转基因小鼠的DA神经元靶标，证明DA信号支持行为条件反射并促进对食物的工具性反应(20-21)。最近，一种Th：Cre转基因大鼠系被开发出来，它允许用光遗传方法(22-23)在更复杂的行为模式中选择性地靶向DA神经元，以便于在大鼠中使用。在这项建议中，我将利用Th：CRE大鼠，结合体内的光遗传学和电生理学，结合复杂的行为分析，探讨DA信号在器质性可卡因摄入和对巴甫洛夫可卡因刺激反应的复吸的不同方面的因果贡献。首先，在目标1中，我建议测试VTA DA神经元激活以调节可卡因自身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信号对可卡因摄取和恢复的必要性。此外，VTA不仅包含DA神经元的异质混合物，还包含相当一部分参与动机加工的非DA神经元(11-19)，但对VTA中不同类别的神经元如何编码药物相关行为知之甚少。因此，在目标3中，我建议描述自我给药和恢复期间光遗传学识别的VTA 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.