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Rationale <p>Despite decades of research and medical development, relapse to drug seeking continues to be a significant challenge in the treatment of substance use disorders. GABA<sub>B</sub> receptor (GABA<sub>B</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<sub>B</sub>-R signaling in DA neurons after exposure to stimulants. Similarly, our recent data demonstrated reduced GABA<sub>B</sub>-R currents in DA neurons during prolonged abstinence from fentanyl vapor self-administration (SA). However, the mechanism of opioid-induced changes in GABA<sub>B</sub>-R currents is not well understood. In addition, GABA<sub>B</sub>-R agonists are plagued with a plethora of side effects limiting their potential clinical use.</p> Objectives <p>In this study we aimed to answer the following questions: first, can we use GABA<sub>B</sub>-R positive allosteric modulators (PAMs) to inhibit relapse to opioid seeking? Secondly, how do opioids result in reduced GABA<sub>B</sub>-R signaling during prolonged abstinence?</p> Approach <p>To this end, we tested the effects of a novel GABA<sub>B</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<sub>B</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. </p> Results <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<sub>2/3</sub>).</p> Conclusion <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<sub>B</sub>-R mediated inhibition of midbrain DA neurons, which is reduced after opioid SA due to reduced GIRK<sub>2/3</sub> expression.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月3日

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  • Narges Pachenari,
  • Amy L. Channell,
  • Andrew J. Belilos,
  • Samuel J. Dienel,
  • Khaled Moussawi

摘要

Rationale

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.

Objectives

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?

Approach

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.

Results

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).

Conclusion

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.