Neural systems mediating competing motivations for cocaine seeking

About This Grant

Individuals with cocaine use disorder frequently experience competing motivations that simultaneously push them to seek out cocaine and push them to not engage in such behavior. Such competing motivations may stem from both a desire for the rewarding nature of the drug and a desire to avoid adverse consequences associated with the drug use. However, the neural systems that mediate decision making under such circumstances are not well understood. The long-term goal of our laboratory is to elucidate the neural systems and networks that underlie the competing motivations for cocaine-seeking behavior, using rat models of cocaine seeking. Our prior work has identified important corticolimbic circuitry involved in the extinction of cocaine seeking after drug self-administration, but such behavioral procedures do not create a simultaneous “in-the-moment” motivational competition. Therefore, for the present proposal, we developed a novel behavioral paradigm in which rats undergo trial-based cocaine self-administration. At the beginning of each trial, a discriminative stimulus (DS) indicates whether an active lever press will produce cocaine or, alternatively, a footshock. After rats acquire this task, they then undergo “competition” tests that consist of DS- cocaine trials, DS-shock trials, and competition trials in which both DS’s and both consequences occur. These procedures will enable us to probe the neural circuits that mediate the decision of whether to engage in cocaine seeking despite a negative consequence (i.e., the competition trials). Prior work has identified the insular cortex as a critical region for drug craving, yet the studies on this region within rodent models, including our own, have been somewhat limited and frequently conflicting. Other evidence reports that the insular cortex is important for decision making “under risk”, suggesting that the previous work examining this region in cocaine seeking did not use the best behavioral models for elucidating its function. Therefore, the present proposal will use our newly developed competing motivations cocaine-seeking model to examine the neural circuits centered on the anterior portion of the insular cortex. In particular, our studies will use temporally precise manipulations of specific inputs to this region and outputs from this region during this task to identify those pathways’ roles during different aspects of the task. Moreover, we will also use neural measures with strong temporal resolution to relate activity in these pathways as well as across a larger network of brain regions to develop a more sophisticated understanding of how these regions communicate during the task. Thus, the proposed studies will provide converging lines of evidence for how these circuits and networks promote and inhibit cocaine seeking depending on the specific circumstances facing the animal.