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Publication
Acute Negative Allosteric Modulation of M5 Muscarinic Acetylcholine Receptors
Inhibits Oxycodone Self-Administration and Cue-Induced Reactivity with No Effect
on Antinociception.
Authors Gould RW, Gunter BW, Bubser M, Matthews RT, Teal LB, Ragland MG, Bridges TM,
Garrison AT, Winder DG, Lindsley CW, Jones CK
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal ACS chemical neuroscience
Year 2019
Date Published 8/1/2019
Volume : Pages 10 : 3740 - 3750
PubMed Reference 31268669
Abstract Opioid use disorder (OUD) is a debilitating neuropsychiatric condition
characterized by compulsive opioid use, dependence, and repeated relapse after
periods of abstinence. Given the high risk of developing OUD following
prescription opioid use, the continued need for opioid-induced analgesia, and
the limitations of current OUD treatments, it is necessary to develop novel,
non-opioid-based treatments for OUD and decrease abuse potential of prescription
opioids. Recent evidence suggests that negative allosteric modulation (NAM) of
the M5 muscarinic acetylcholine receptor (M5 mAChR) may provide an alternative
therapeutic approach for the treatment of OUD. Previous studies demonstrated
localization of M5 mAChR expression within the mesocorticolimbic reward
circuitry and that the selective M5 NAM ML375 attenuates both cocaine and
alcohol self-administration in rats. In the present study, the effects of ML375
were evaluated in rats self-administering the µ-opioid agonists oxycodone or
remifentanil on a progressive ratio (PR) schedule or on cue reactivity (a rodent
model of relapse) in the absence of oxycodone following 72 h of abstinence.
ML375 reduced the PR break point for oxycodone and remifentanil
self-administration and attenuated cue-elicited responding. Importantly, ML375
did not affect sucrose pellet-maintained responding on a PR schedule or
opioid-induced antinociception using the hot-plate and tail-flick assays. We
also confirm expression of M5 mAChR mRNA in the ventral tegmental area and show
that this is primarily on dopamine (tyrosine hydroxylase mRNA-positive) neurons.
Taken together, these findings suggest that selective functional antagonism of
the M5 mAChR may represent a novel, non-opioid-based treatment for OUD.




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