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.
A major problem in the treatment of severe anxiety is the hyper-responsiveness to fear-inducing environmental triggers, even after protracted remission periods. Clinical experience indicates that there are few effective approaches for use in crisis intervention, stabilization and harm reduction in at-risk populations. By employing new pharmacological tools with promising therapeutic value in a broad spectrum of anxiety-related conditions, a better understanding of the neurobiological mechanisms triggering maladaptive fear renewal in the treatment of anxiety disorders will be gained.
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