Acute Negative Allosteric Modulation of M₅ Muscarinic Acetylcholine Receptors Inhibits Oxycodone Self-Administration and Cue-Induced Reactivity with No Effect on Antinociception

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 opioidinduced 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 M 5 muscarinic acetylcholine receptor (M 5 mAChR) may provide an alternative therapeutic approach for the treatment of OUD. Previous studies demonstrated localization of M 5 mAChR expression within the mesocorticolimbic reward circuitry and that the selective M 5 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 hours of abstinence. ML375 reduced the PR break point for oxycodone and remifentanil self-administration and attenuated cue-elicited responding. Importantly, ML375

Muscarinic M4 and M5 receptors in the ventral subiculum differentially modulate alcohol seeking versus consumption in male alcohol‐preferring rats

“…Recently, several subtype‐selective, allosteric modulators of muscarinic receptors have been developed, enhancing the ability to examine specific behavioural roles of the different muscarinic receptors in affective disorders (Bender, Garrison, & Lindsley, 2018; Berizzi et al, 2016; Gentry et al, 2013; Gould et al, 2019; Langmead & Christopoulos, 2014; Walker & Lawrence, 2020). The selective M 4 receptor PAM, VU0467154, possesses both cognitive enhancing and antipsychotic‐like effects (Bubser et al, 2014; Gould et al, 2018) and reduces alcohol consumption and seeking when administered systemically, or within the dorsolateral striatum (Walker et al, 2020).…”

Loss of muscarinic M5 receptor function manifests disparate impairments in exploratory behavior in male and female mice despite common dopamine regulation

“…Indeed, negative and positive allosteric modulators targeted toward the M5 receptor are actively being developed (Bridges et al, 2010; Bridges et al, 2009; Gentry et al, 2010a; Gentry et al, 2013; Gentry et al, 2010b; Gentry et al, 2010c; Gentry et al, 2014). Manipulations of M5 receptor function have indicated that it may play a role in drug seeking and taking, as well as sensorimotor gating (Basile et al, 2002; Gould et al, 2019; Gunter et al, 2018; Thomsen et al, 2005; Thomsen et al, 2007). However, much remains unknown with respect to more basic characterization of cellular and behavioral functioning for the M5 receptor, with little attention paid to potential sex differences.…”

“…Reduction or ablation of M5 receptor function leads to reduced stimulant-induced psychomotor activation, drug seeking and drug taking (Basile et al, 2002; Fink-Jensen et al, 2003; Gould et al, 2019; Gunter et al, 2018; Thomsen et al, 2005). This appears to be the case for psychostimulants, alcohol, and opioids, revealing a broad impact of these muscarinic receptors as therapeutic target for substance use disorders.…”

Cholinergic and dopaminergic‐mediated motivated behavior in healthy states and in substance use and mood disorders

“…activational motivation) for a drug reinforcer, which may not be captured by the CPP and 2 BC (Hodos 1961; Schuster & Thompson, 1969). Interference with ACh, particularly the M5 mAChRs have also been shown to decrease the strength of the drug reinforcer, such as cocaine, by decreasing break point responding on a progressive ratio self‐administration task (Gunter et al, 2018; Gould et al, 2019). Thus, M5 mAChRs may be mediating activational characteristics of cocaine motivation.…”