Reduced GIRK expression in midbrain dopamine neurons during prolonged abstinence from fentanyl self-administration.

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Despite decades of research and medical development, relapse to drug seeking continues to be a significant challenge in the treatment of substance use disorders. GABAB receptor (GABAB-R) agonists have been shown preclinically to inhibit relapse by acting on midbrain dopamine (DA) neurons and are sometimes used off-label for the treatment of alcohol use disorder. Studies in rodent models show reduced GABAB-R signaling in DA neurons after exposure to stimulants. Similarly, our recent data demonstrated reduced GABAB-R currents in DA neurons during prolonged abstinence from fentanyl vapor self-administration (SA). However, the mechanism of opioid-induced changes in GABAB-R currents is not well understood. In addition, GABAB-R agonists are plagued with a plethora of side effects limiting their potential clinical use. In this study we aimed to answer the following questions: first, can we use GABAB-R positive allosteric modulators (PAMs) to inhibit relapse to opioid seeking? Secondly, how do opioids result in reduced GABAB-R signaling during prolonged abstinence? To this end, we tested the effects of a novel GABAB-R PAM (KK-92A) on reinstatement of drug seeking in a rat model of intravenous (IV) fentanyl SA. Using in situ hybridization with RNAscope, we examined the effects of opioids on mRNA levels of various genes involved in GABAB-R signaling, in two rodent models of opioid addiction including a rat model of IV fentanyl SA and a mouse model of fentanyl vapor SA. Our results show that KK-92A inhibits relapse to fentanyl but not sucrose-seeking in rats, and fentanyl SA results in reduced mRNA levels of the G protein-coupled inwardly rectifying potassium channel subtypes 2 and 3 (GIRK2/3). These findings suggest that PAMs like KK-92A are a potential therapeutic strategy for opioid use disorder and their effect is likely due to rectifying GABAB-R mediated inhibition of midbrain DA neurons, which is reduced after opioid SA due to reduced GIRK2/3 expression.