The glucocorticoid receptor (GR) is best known for its role in mediating the stress response. Thus, it is not surprising that this receptor has been implicated in the pathophysiology of several psychiatric disorders. Recently, a number of reports have emerged identifying GR-related polymorphisms associated with susceptibility to cocaine use and addiction. Indeed, it has been known for decades that glucocorticoids, via GR, interact with dopamine to produce individual differences in response to drugs of abuse. The mechanism by which this occurs, however, remains to be determined. Importantly, while stress can facilitate dopamine- glucocorticoid interactions, it is not necessary. That is, an individual may be inherently ?wired?, or primed for these interactions to occur, rendering them more susceptible to addiction, even in the absence of stress. The overarching goal of the proposed work is to identify one such priming mechanism. Some individuals may be particularly prone to addiction because they have a tendency to attribute drug cues with excessive incentive motivational value. For these individual exposure to cues (e.g. paraphernalia) previously associated with drug- taking may precipitate relapse, despite a desire to remain abstinent. In rats, we have shown that those with an increase propensity for incentive learning have insufficient ?top-down? cortical control, concurrent with hyperactive subcortical mechanisms. In conjunction, these rats are more impulsive, have deficits in attentional control and are more likely to exhibit cue-induced reinstatement of drug-seeking behavior (i.e. relapse). The neurobehavioral endophenotype captured by the propensity to attribute incentive salience to reward cues, therefore, is reminiscent of individuals with addiction. The central hypothesis to be tested here is that GR function in a ?top-down? cortico-striatal circuit plays a critical role in determining this addiction-related endophenotype. We will take advantage of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas 9-mediated gene-editing technology to selectively manipulate GR in glutamatergic afferents projecting from the prelimbic cortex (PrL) to the nucleus accumbens core (NAcC) - a circuit that we believe has little to do with stress responsivity and more to do with mediating responses to reward-associated cues. We hypothesize that knockdown of GR selectively in this cortico-striatal circuit will attenuate 1) the propensity to attribute incentive motivational value to a reward cue, and 2) cue-induced reinstatement of cocaine-seeking behavior. This exploratory grant has the potential to uncover a novel neural mechanism that contributes to the propensity for relapse. Regardless of the outcome, this research will set a foundation for future studies to further investigate the role of GR in addiction-related behaviors with great neuroanatomical precision.
This research aims to uncover neural mechanisms that render some individuals more susceptible to addiction. We will utilize new tools that enable us to precisely probe brain-behavior relationships and identify critical components of the neural circuitry that subserves complex behaviors of relevance to addiction. The findings from these studies will enhance our understanding of the pathophysiology of substance abuse and could lead to novel targets for the treatment of addiction.