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Hypocretin Receptor 1 Blockade Early in Abstinence Prevents Incubation of Cocaine Seeking and Normalizes Dopamine Transmission
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Hypocretin Receptor 1 Blockade Early in Abstinence Prevents Incubation of Cocaine Seeking and Normalizes Dopamine Transmission

Philip Clark, Volodar Migovich, Sanjay Das, Wei Xu, Sandhya Kortagere and Rodrigo España
bioRxiv
01 Dec 2024
DOI: https://doi.org/10.1101/2024.11.30.625912
PMID: 39651183
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623669View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Abstinence Adaptation Mesolimbic system Nucleus accumbens Orexin receptors Orexins Cocaine Dopamine
Abstinence from cocaine use has been shown to elicit a progressive intensification or "incubation" of cocaine craving/seeking that is posited to contribute to the propensity for relapse. While the mechanisms underlying incubation of cocaine seeking remain elusive, considerable evidence suggests that abstinence from cocaine promotes mesolimbic dopamine adaptations that may contribute to exaggerated cocaine seeking. Consequently, preventing these dopamine adaptations may reduce incubation of cocaine seeking. In the present studies we first examined if incubation of cocaine seeking was associated with aberrant dopamine transmission in the nucleus accumbens after seven days of abstinence from intermittent access to cocaine. Given the extensive evidence that hypocretins/orexins regulate motivation for cocaine, we then examined to what extent hypocretin receptor 1 antagonism on the first day of abstinence prevented incubation of cocaine seeking and dopamine adaptations later in abstinence. Results indicated that abstinence from intermittent access to cocaine engendered robust incubation of cocaine seeking in both female and male rats. We also observed aberrant dopamine transmission only in rats that displayed incubation of cocaine seeking. Further, we showed that a single injection of the hypocretin receptor 1 antagonist, RTIOX-276, on the first day of abstinence prevented incubation of cocaine seeking and aberrant dopamine transmission. These findings suggest that hypocretin receptor 1 antagonism may serve as a viable therapeutic for reducing cocaine craving/seeking, thus reducing the likelihood for relapse.Competing Interest StatementThe authors have declared no competing interest.

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