Saturday, April 27, 2024
4/27/2024
Project Summary/Abstract Cocaine use disorder is a chronic disease and currently no approved pharmacotherapies exist for its treatment. Among the greatest challenges in the treatment of cocaine use disorder is prevention of relapse to drug use. In rats, periods of abstinence following cocaine use intensifies seeking and motivation for drug, which has been associated with increased propensity for relapse. Although extensive evidence indicates that mesolimbic dopamine influences cocaine reinforcement, the involvement of dopamine in the regulation of sleep has received comparatively less attention. We recently demonstrated that the dopamine transporter governs diurnal fluctuations in extracellular dopamine tone in the nucleus accumbens and that dopamine uptake fluctuates across the sleep/wake cycle, which impacts the effects of cocaine at inhibiting the dopamine transporter. Moreover, our preliminary and recently published data suggest that sleep disturbances that occur during abstinence promote cocaine seeking and that alterations in dopamine transporter function in the nucleus accumbens may contribute to these effects. Together, these findings raise the possibility that dopamine neurotransmission in the nucleus accumbens may function as a node that integrates both motivational and sleep/wake processes. In the proposed studies, we hypothesize that cocaine-related sleep disruptions during abstinence contribute to dopamine transporter adaptations that promote incubation of cocaine seeking and increase dopamine transporter sensitivity to cocaine. Further, we propose that restoration of rapid-eye movement sleep and/or normalization of dopamine transporter function during abstinence will attenuate incubation of cocaine seeking and reduce dopamine transporter sensitivity to cocaine. Completion of the proposed experiments will offer new insights into the link between sleep disruptions and development of cocaine seeking, and the extent to which this involves alterations in dopamine neurotransmission in the nucleus accumbens. Consequently, expected results should significantly inform the field and help to identify future treatment strategies for cocaine use disorder.
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