Acute Negative Allosteric Modulation of M5 Muscarinic Acetylcholine Receptors Inhibits Oxycodone Self-Administration
and Cue-Induced Reactivity with No Effect on Antinociception
posted on 2019-07-24, 19:13authored byRobert
W. Gould, Barak W. Gunter, Michael Bubser, Robert T. Matthews, Laura B. Teal, Madeline G. Ragland, Thomas M. Bridges, Aaron T. Garrison, Danny G. Winder, Craig W. Lindsley, Carrie K. Jones
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.