Narges Pachenari, Amy L Channell, Andrew J Belilos, Samuel J Dienel, Khaled Moussawi
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引用次数: 0
Abstract
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.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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