Thursday, April 25, 2024
4/25/2024
Abstract DAT18-07 Opiate abuse has become an extremely deadly and costly public health epidemic. The best available tools for treating opiate addiction are limited and have improved little in recent decades. Innovative research is therefore needed to spur the development of new therapeutic strategies. Given the complex, multifaceted nature of addiction, it is crucial to develop selective, well-controlled animal models of the specific psychological mechanisms that contribute to problematic drug use and relapse, as well as the apathy (i.e., loss of motivation for adaptive, rewarding activities) that often accompanies long-term drug taking and withdrawal. Clinical studies have shown that drug-associated cues can bias attention and disrupt cognition, but there has been relatively little animal research on this subject. We suggest that this cognitive disruption removes an important source of behavioral control, increasing the probability that decisions will be made impulsively, without fully considering the consequences of one’s actions. Our proposal will test the hypothesis that opiate-paired contextual cues transiently disrupt goal-directed decision-making. Our preliminary data provide strong support for this hypothesis and demonstrate the feasibility of our approach. Aim 1 will extend this work to establish a new behavioral protocol to characterize the tendency for cues paired with morphine to disrupt rats’ capacity for goal-directed action selection, which will be assayed using the well-established outcome devaluation task. We will also investigate two hypotheses about the specific mechanisms that underlie this disruptive behavioral influence of morphine- paired cues. One possibility is that such cues directly interfere with rats' capacity for goal-directed action by perturbing dorsomedial striatum (DMS) function, which is known to play a fundamental role in this aspect of decision making. Alternatively, morphine-paired cues may merely shift the balance in behavioral control from the DMS to the dorsolateral striatum (DLS), which supports automatic, habitual behavior. We will test these hypotheses in Aim 1 by investigating how morphine-paired cues impact neuronal activation (c-Fos expression) within the DMS and DLS. Aim 2 will investigate these accounts further using a chemogenetic approach to selectively inhibit DMS or DLS neurons at test. This will allow us to determine if DLS inactivation restores goal- directed action selection (and associated DMS neural activation) when morphine-paired cues are present. Our findings will improve understanding of the specific psychological and neural mechanisms of behavioral dysregulation caused by opiate cue exposure, and may guide future efforts to develop more targeted strategies for combating opiate addiction. This work will also serve as the foundation for a separate R01 proposal to study the specific neural circuits (and adaptations) mediating this important but poorly understood aspect of addiction.
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