Mechanisms of dopaminergic dysfunction in substance use disorder

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PROJECT SUMMARY/ABSTRACT The mesolimbic dopamine system is at the core of reinforcement learning, and its dysregulation by stimulants is a major factor in the development of cocaine use disorder (CUD). While dopamine is often linked to valence- based learning, emerging data - as well as preliminary data in this proposal - has indicated that dopamine release in the NAc core is evoked by both rewarding and aversive stimuli, thus challenging the idea of bi- directional valence coding. It is likely that dopamine release in the NAc core signifies how salient – or important – a stimulus is independ`ent of its positive or negative emotional value (valence). Salience is a key driver of the speed at which information is learned in an environment; thus, deficits in a system that encodes saliency would slow many forms of learning - both drug and non-drug associated. If NAc core dopamine signals saliency, rather than a valence-based signal, aberrations in this system could explain several CUD-associated learning deficits. For example, deficits in salience attribution would slow learning of new contingencies while leaving previously learned reward-seeking behaviors, such as drug seeking, intact. Indeed, individuals with CUD exhibit deficits in fundamental behavioral functions following repeated drug exposure that extend to non-drug associated stimuli. These deficits in fundamental behavioral functions negatively affect the lives of individuals suffering from CUD, and the severity of these symptoms is strongly associated with disease progression and treatment outcomes. Thus, to determine the contribution of NAc core dopamine deficits to CUD symptomology, it is critical to first understand the role of NAc core dopamine in basic stimulus processing and learning. Next it will be important to understand how repeated drug exposure dysregulates these basic processes to cause these deficits. In both rodents and humans, long-term cocaine exposure leads to reduced responsiveness of NAc dopamine at baseline and to environmental stimuli. Our overarching framework is that cocaine use increases behavior directed towards drug-associated stimuli, in part, by weakening of the salience of non-drug associated events. We will combine optical tools for recording and manipulating dopamine release in the NAc core of mice during behavioral tasks that dissociate valence from behavioral action and saliency to understand how dopamine drives learning. Next, we will conduct a series of experiments to understand how valence-based and valence-free learning recruits dopamine release to influence behavior. Finally, we will outline how cocaine self-administration dysregulates dopamine responses to non-drug stimuli to drive punishment resistance and deficits in new reward learning. Together these studies will define how cocaine self-administration alters stimulus processing to drive behaviors characteristic of CUD.