Targeted chemogenetic stimulation of rat VTA GABA neurons in cocaine extinction and reinstatement

大鼠 VTA GABA 神经元的靶向化学遗传学刺激可卡因消除和恢复

基本信息

批准号：
9386981
负责人：
Caroline Evelyn Bass
金额：
$ 23.93万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386981
关键词：
Affect Alcohols Behavior Brain Brain region Cells Cocaine Cocaine Dependence Consumption Cues Data Discrimination Extinction (Psychology)Female Future GAD67 enzyme Gene Expression Gene Targeting Genetic Glutamate Decarboxylase Heroin Incentives Infusion procedures Interneurons Laboratories Mediating Modeling Mus Neurons Nucleus Accumbens Optics Outcome Pharmaceutical Preparations Pilot Projects Process Psychological reinforcement Rattus Relapse Rewards Role Self Administration Self-Administered Sex Characteristics Site Stimulus Sucrose Synapses System Therapeutic Intervention Training Transgenic Mice Ventral Tegmental Area Viral Viral Vector Virus adeno-associated viral vector alcohol seeking behavior behavioral response cholinergic classical conditioning combinatorial craving designer receptors exclusively activated by designer drugs dopaminergic neuron drug reward drug seeking behavior experimental study gamma-Aminobutyric Acid innovation learning extinction male motivated behavior novel novel therapeutic intervention optogenetics preference relating to nervous system reward processing targeted treatment transmission process vector

项目摘要

Dopaminergic neurons originating from the ventral tegmental area (VTA) regulate a variety of reward and drug- related behaviors. However, up to 20% of VTA neurons are GABAergic interneurons, and ~5% are GABA projection neurons (GPNs) that send projections to several brain regions involved in drug reward, including the nucleus accumbens (NAc). Recently the role of VTA GABA neurons and GPNs in reinforcement has been explored using transgenic mice that allow for selective manipulation of VTA GABA neurons. However, the role of these GABAergic neurons in drug-related behaviors is much less understood. We propose to use a novel combinatorial adeno-associated viral (AAV) vector system to target gene expression to either VTA GABA neurons or VTAàNAc core GPNs in wildtype rats that have been trained to self-administer cocaine. The targeted GABA neurons will express DREADDs (designer receptors exclusively activated by designer drugs) which will allow us to selectively stimulate these neuronal subtypes during extinction of cocaine self- administration, and reinstatement of cocaine-seeking behavior, a rat model of relapse. We hypothesize that VTA GABA neurons will enhance responding during extinction learning and cocaine- and cue-induced reinstatement by disrupting learned cue-reward associations. Furthermore, we believe that VTAàNAc core GPN activation will selectively enhance cue-induced reinstatement, but have little influence on cocaine-induced reinstatement or extinction. In aim 1 of this proposal, we will determine the role of VTA GABA neurons in extinction learning and reinstatement of cocaine-seeking. We will also undertake a pilot study in female rats to determine if sex differences exist. In aim 2 we will selectively target the VTA GPNs projecting to the NAc core. By contrasting these results of aim 1 and 2, we will determine if the VTAàNAc core GPN effects differ substantially from stimulating all VTA GABA neurons, and whether these specific projections alone may serve as a potential target for therapeutic intervention. These experiments will establish the role of VTA GABA neurons in drug-seeking behaviors, and will provide the necessary groundwork for future exploration into the mechanisms underlying VTA GABA neuron effects on responding to drug cues and the processes underlying relapse.

源自腹侧对盖区域（VTA）的多巴胺能神经元调节多种奖励和药物相关行为。但是，多达20％的VTA神经元是GABA能中间神经元，〜5％是GABA 投射神经元（GPN）将投影发送给参与药物奖励的几个大脑区域，包括伏隔核（NAC）。最近使用转基因小鼠进行探索，以选择性操纵VTA GABA神经元。但是，角色这些与药物相关行为中的GABA能神经元中的理解要少得多。我们建议使用小说组合腺体相关病毒（AAV）载体系统以靶向基因表达到任何一个VTA GABA 野生型大鼠中的神经元或vtaàNAC核心GPN被训练为自动可卡因。这有针对性的GABA神经元将表达Dreadds（设计师药物专门激活的设计师接受者）这将使我们能够在可卡因自我灭绝期间选择性地刺激这些神经元亚型给药和恢复可卡因的寻求行为，这是一种大鼠复发模型。我们假设这一点 VTA GABA神经元将在扩展学习期间增强反应以及可卡因和提示诱导的通过破坏学习的提示奖励关联来恢复原状。此外，我们认为vtaàNAC核心 GPN激活将有选择地增强提示引起的恢复，但对可卡因诱导的影响很小恢复或灭绝。在本提案的目标1中，我们将确定VTA GABA神经元在扩展学习和寻求可卡因的恢复。我们还将在女性大鼠中进行一项试点研究确定是否存在性别差异。在AIM 2中，我们将选择性地针对投影到NAC核心的VTA GPN。通过将AIM 1和2的这些结果进行对比，我们将确定VTAàNAC核心GPN是否影响不同基本上是通过刺激所有VTA GABA神经元，以及仅这些特定项目是否可以服务作为治疗干预的潜在目标。这些实验将确定VTA GABA的作用寻求毒品行为的神经元，并将为将来探索的必要基础提供 VTA GABA神经元对响应药物提示的效应和依据的过程复发。