Endogenous cannabinoid control of reward substrates

项目总结 伏隔核多巴胺的时相释放传统上与动机有关 由食物等主要奖励驱动的行为。然而，关于这一问题的调查却较少。 反常条件化的线索与动机网络相结合。这一点值得注意，因为避免了令人厌恶的刺激 可以是高度激励的，因为伏隔核是一个边缘-运动接口，连接着几个 恐惧网络的关键节点。我们实验室最近的工作支持了阶段累积物的重要作用 在避免惩罚的情况下释放多巴胺。具体地说，在关联的提示期间，释放被抑制 伴随着恐惧，并在与主动回避有关的线索上得到增强。从理论上讲，多巴胺有助于 这些过程通过调节习得的联想对工具性反应的激励作用， 行为发生所必需的机制。上一个资金周期的数据显示， 腹侧被盖纹状线索中的内源性大麻素诱导伏隔多巴胺释放激增 寻求奖赏，很可能是通过解除对多巴胺细胞的抑制。因为全身性大麻素受体 阻断会损害主动回避，这一机制也可能被用来促进多巴胺在 逃避惩罚。在这里，我们提出了三个实验来研究多巴胺释放的作用 伏隔核及其与大麻素受体在厌恶反应中的相互作用 刺激物。首先，我们将评估在主动回避过程中看到的释放模式是否符合以下理论 多巴胺及其是否会对行为产生因果影响(目标1)。接下来，我们将确定大脑轨迹和 内源性大麻素在回避过程中的作用机制及其如何调节线索-- 诱发多巴胺释放(AIM 2)。在目标3中，我们将通过以下方式提供对这些问题的进一步机械性见解 确定负责内源性大麻素介导效应伏隔信号的多巴胺受体 主动回避。这些研究问题从未被直接研究过，因为这样做需要 对精确的解剖框架进行选择性调制。在这里，我们将干扰或促进 腹侧被盖的内源性大麻素张力，而对多巴胺神经元的额外光遗传控制将 允许对与内源性大麻素功能相关的当前假设进行显式测试。因此，通过研究多巴胺 在厌恶刺激期间与内源性大麻素的相互作用，目前的提议还没有使用工具 应用于这些问题，以产生对治疗障碍的治疗策略的新见解 涉及严重的焦虑成分，如强迫寻求毒品。

PROJECT SUMMARY Phasic dopamine release in the nucleus accumbens has traditionally been associated with motivated behaviors driven by primary rewards such as food. However, there has been less investigation regarding how aversively conditioned cues engage motivational networks. This is notable since avoidance of aversive stimuli can be highly motivating and because the nucleus accumbens is a limbic-motor interface connected to several key nodes of the fear network. Recent work from our laboratory supports an important role for phasic accumbal dopamine release in the avoidance of punishment. Specifically, release is suppressed during cues associated with fear and enhanced upon cues linked to active avoidance. It is theorized that dopamine contributes to these processes by modulating the invigorating action of learned associations on instrumental responding, a mechanism essential for behavior to occur. Data from the previous funding cycle showed that endocannabinoids in the ventral tegmentum sculpt cue-induced accumbal surges in dopamine release during reward seeking, likely through disinhibition of dopamine cells. Because systemic cannabinoid receptor blockade impairs active avoidance, this mechanism may also be recruited to enhance dopamine release during the avoidance of punishment. Here, we propose three experiments to investigate the role of dopamine release in the nucleus accumbens and its interaction with cannabinoid receptor signaling during responses to aversive stimuli. First, we will assess if patterns of release seen during active avoidance conform to theories involving dopamine and whether they causally influence behavior (aim 1). Next, we will determine the brain loci and the mechanisms responsible for the actions of endocannabinoids during avoidance and how they modulate cue- evoked dopamine release (aim 2). In aim 3 we will provide further mechanistic insight to these questions by determining the dopamine receptors responsible for accumbal signaling of endocannabinoid-mediated effects in active avoidance. These research questions have never been directly examined because doing so requires selective modulation of precise anatomical frameworks. Here, we will interfere with or facilitate endocannabinoid tone in the ventral tegmentum while additional optogenetic control of dopamine neurons will allow explicit tests of current hypotheses related to endocannabinoid function. Thus, by investigating dopamine interactions with endocannabinoids during aversive stimuli, the present proposal makes use of tools not yet applied to these questions to generate new insights on therapeutic strategies for the treatment of disorders involving a severe anxiety component such as compulsive drug seeking.