Ventral tegmental area dopamine in cocaine self administration and relapse

腹侧被盖区多巴胺在可卡因自我给药和复发中的作用

• 批准号: 9116811
• 负责人: Benjamin Thomas Saunders
• 金额: $ 5.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116811
• 关键词: Address; Attention; Attenuated; Behavior; Behavioral; Behavioral Paradigm; Brain; Cells; Cocaine; Complex; Corpus striatum structure; Cues; Development; Dopamine; Dopamine Antagonists; Drug usage; Electrophysiology (science); Food; Fostering; Future; Glutamates; Goals; Halorhodopsins; Health; Human; Intake; Learning; Light; Maintenance; Methods; Midbrain structure; Motivation; Neurons; Nucleus Accumbens; Optics; Pattern; Pharmaceutical Preparations; Physiology; Population; Probability; Process; Prosencephalon; Public Health; Rattus; Relapse; Rewards; Role; Self Administration; Signal Pathway; Signal Transduction; Specificity; Stimulus; Structure; Techniques; Testing; Training; Transgenic Mice; Transgenic Organisms; United States; Ventral Tegmental Area; addiction; cell type; conditioning; craving; dopamine system; dopaminergic neuron; drug craving; drug relapse; in vivo; insight; motivational processes; novel; optogenetics; preclinical study; preference; research study; response; therapeutic target; tool

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.

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多的关注，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 细胞或伏隔核等区域中的 DA 末端的破坏会破坏药物的自我给药 (5-6)，并且给予 DA 受体拮抗剂会减弱药物相关刺激促进恢复的能力 (7)。在人类成瘾者中，纹状体响应药​​物相关刺激而释放 DA 与药物渴望增加和未来复发相关 (8,9)。尽管 DA 通常与吸毒和复发有关，但迄今为止，DA 系统尚未按照分离其在这些行为的特定方面的作用所需的时间精度和细胞类型特异性进行操作。光遗传学工具已应用于转基因小鼠的靶向 DA 神经元，证明 DA 信号传导支持行为调节并促进对食物的仪器反应 (20-21)。最近，开发了一种 Th:Cre 转基因大鼠系，它允许在针对大鼠使用而优化的更复杂的行为范例中，通过光遗传学方法 (22-23) 选择性靶向 DA 神经元。在本提案中，我将利用 Th:Cre 大鼠，将体内光遗传学和电生理学与复杂的行为分析相结合，探讨 DA 信号传导对工具性可卡因摄入和对巴甫洛夫可卡因刺激的反应的复发的不同方面的因果贡献。首先，在目标 1 中，我建议测试 VTA DA 神经元激活是否足以调节可卡因自我给药和可卡因提示诱导的恢复。其次，在目标 2 中，我建议通过抑制 VTA DA 神经元来测试 DA 信号传导对于可卡因摄入和恢复的必要性。此外，VTA 不仅包含 DA 神经元的异质混合物，还包含很大一部分有助于动机处理的非 DA 神经元 (11-19)，但人们对 VTA 中不同神经元群如何编码药物相关行为知之甚少。因此，在目标 3 中，我建议描述光遗传学识别的 VTA DA 神经元 (16) 在自我管理和恢复过程中的放电模式。