Drug addiction is a chronically relapsing disorder that often has devastating consequences for the addicted person and society as a whole. In particular, during periods of drug abstinence, drug-associated stimuli or general feelings of stress may elicit powerful feelings of craving in drug-dependent individuals. Indeed, stress is a particularly potent trigger because, unlike drug cues (e.g., paraphernalia) and contexts (i.e., places where drugs are obtained or used) which can be avoided, stress is unavoidable in non-drug contexts such as work, family, or finances. In most conditions, these stressful encounters are aversive and unavoidable, and can create a heightened anxiety state that addicted individuals attempt to alleviate by relapse to a drug-taking episode. However, in contrast to these inescapable stressors, in some situations it is possible to have control over an aversive situation. These controllable stressors, while still aversive, nonetheless have been shown to endow subjects with trans-situational resilience against future stressors. In an animal model of stressor controllability, rats can rotate a wheel to terminate an aversive tailshock (escapable shock; ES). Physically yoked animals receive the same shocks as the ES subjects, but are unable to control the experience, and thus perceive the shock as inescapable (IS). After a single ES session, rats show decreased fear reactivity in fear conditioning, conditioned social defeat compared to IS subjects and even non-stressed controls. While much is known about how uncontrollable stressors can potentiate drug-taking and relapse, little is known about whether ES experience may reverse these negative consequences. Here we report that while rats with a history of repeated cocaine self-administration display impaired neural signaling in the NAc as well as poor acquisition of higher-order associations, these deficits can be prevented or reversed by a single ES experience during the abstinence period, while also decreasing drug seeking in extinction. These control-related effects may derive from functionally overlapping set of circuits between the NAc, prefrontal cortex (PFC) and ventral tegmental area (VTA). This set of structures is known to support motivated learning and stress-induced drug relapse, and while PFC is critical for controllabilty, less is known about whether NAc or VTA also contribute to these processes. To fully characterize this phenomenon, I will first identify how neural signaling in the PFC encodes control-related information and whether this is related to recovered function in motivated learning and resistance to drug relapse. Next, we will use optogenetics to determine the necessity of PFC-to-NAc pathways in establishing the neuroprotective-like effects of control on subsequent learning and relapse. Finally, I will use TH::cre rats to determine whether dopamine signaling is critical for the acquisition and later expression of control-related benefits in motivation and relapse. These findings suggest that controllability may provide a potential therapeutic intervention with clinical implications, while also providing powerful insights into the neural circuits that support stress, addiction and resilience in both drug-experienced and drug-nave populations.
PUBLIC HEALTH RELEVANCE: Drug addiction is a chronically relapsing disorder that affects millions of people every year; a central tragedy of this serious mental illness is a loss of control whereby individuals will resume drug taking despite sincere desire to quit. Previous work has shown that chronic experience with drugs of abuse persistently alters the function of learning and motivational circuits in the brain, making these individuals more susceptible to subsequent relapse. This work will explore how experience with a controllable stressful event may rescue the function of these circuits and thereby reverse drug-related cognitive deficits and decrease the probability of relapse.
