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GABA<jats:sub>B<\/jats:sub> receptor (GABA<jats:sub>B<\/jats:sub>-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 GABA<jats:sub>B<\/jats:sub>-R signaling in DA neurons after exposure to stimulants. Similarly, our recent data demonstrated reduced GABA<jats:sub>B<\/jats:sub>-R currents in DA neurons during prolonged abstinence from fentanyl vapor self-administration (SA). However, the mechanism of opioid-induced changes in GABA<jats:sub>B<\/jats:sub>-R currents is not well understood. In addition, GABA<jats:sub>B<\/jats:sub>-R agonists are plagued with a plethora of side effects limiting their potential clinical use.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objectives<\/jats:title>\n            <jats:p>In this study we aimed to answer the following questions: first, can we use GABA<jats:sub>B<\/jats:sub>-R positive allosteric modulators (PAMs) to inhibit relapse to opioid seeking? Secondly, how do opioids result in reduced GABA<jats:sub>B<\/jats:sub>-R signaling during prolonged abstinence?<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach<\/jats:title>\n            <jats:p>To this end, we tested the effects of a novel GABA<jats:sub>B<\/jats:sub>-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 GABA<jats:sub>B<\/jats:sub>-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. <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>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 (GIRK<jats:sub>2\/3<\/jats:sub>).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>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 GABA<jats:sub>B<\/jats:sub>-R mediated inhibition of midbrain DA neurons, which is reduced after opioid SA due to reduced GIRK<jats:sub>2\/3<\/jats:sub> expression.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00213-025-06747-5","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T05:20:43Z","timestamp":1738560043000},"page":"1653-1666","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reduced GIRK expression in midbrain dopamine neurons during prolonged abstinence from fentanyl self-administration"],"prefix":"10.1007","volume":"242","author":[{"given":"Narges","family":"Pachenari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Channell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Belilos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Dienel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6378-0428","authenticated-orcid":false,"given":"Khaled","family":"Moussawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"key":"6747_CR1","doi-asserted-by":"publisher","first-page":"12251","DOI":"10.1523\/JNEUROSCI.0494-11.2011","volume":"31","author":"D Arora","year":"2011","unstructured":"Arora D, Hearing M, Haluk DM, Mirkovic K, Fajardo-Serrano A, Wessendorf MW et al (2011) Acute Cocaine Exposure Weakens GABA B Receptor-Dependent G-Protein-Gated Inwardly Rectifying K + Signaling in Dopamine Neurons of the Ventral Tegmental Area. 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