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

基本信息

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
项目类别：
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

项目摘要

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了极大的关注，包括寻求药物的动机和响应与药物相关的线索的复发（1-4）。腹侧盖区域（VTA）中DA细胞的破坏或诸如伏隔核的区域的DA末端破坏了药物自我给药（5-6）和DA受体拮抗剂的给药可减弱药物相关刺激促进恢复的能力（7）。在人类吸毒者中，响应与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有关（8,9）。尽管DA通常与药物服用和复发有关，但迄今为止，DA系统尚未通过时间精度和细胞类型的特异性来操纵，以隔离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中的DA神经元，表明DA信号支持行为调节并促进食物的仪器反应（20-21）。最近，开发了一种Cre Cre trengic Ratline，可以在更复杂的行为范式中选择性靶向DA神经元，以优化用于大鼠的更复杂的行为范式。在此提案中，我将利用：将体内光遗传学和电生理学与复杂的行为分析结合起来，探测DA信号传导对工具可卡因摄入不同方面的因果关系，并响应Pavlovian Cocaine刺激性刺激。首先，在AIM 1中，我建议测试VTA DA神经元激活的充分性，以调节可卡因自我给药和可卡因提示引起的恢复。其次，在AIM 2中，我建议通过抑制VTA DA神经元来测试DA信号的必要性，以进行可卡因的摄入和恢复。此外，VTA不仅包含DA神经元的异质混合物，而且还包含有助于动机加工的非DA神经元的大量非DA神经元（11-19），但对VTA编码药物相关行为中不同神经元种群的不同知之甚少。因此，在AIM 3中，我建议在自我管理和恢复期间表征射击模式在光遗传学上识别的VTA DA神经元（16）。