Contrasting effects of the α7 nicotinic receptor antagonist methyllycaconitine in different rat models of heroin reinstatement.

Josephine Palandri,Sue Wonnacott,Chris P Bailey,David J Heal,Sharon L Smith

doi:10.1177/0269881121991570

Abstract

Background:α7 Nicotinic acetylcholine receptors are implicated in the reinstatement of drug-seeking, an important component of relapse. We showed previously that the α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, specifically attenuated morphine-primed reinstatement of conditioned place preference in rodents and this effect was mediated in the ventral hippocampus.Aims:The purpose of this study was to evaluate α7 nicotinic acetylcholine receptor antagonism in reinstatement of the conditioned place preference for the more widely abused opioid, heroin, and to compare the effect of α7 nicotinic acetylcholine receptor blockade on reinstatement of heroin-seeking and heroin self-administration in an intravenous self-administration model of addictive behaviour.Methods:Rats were trained to acquire heroin conditioned place preference or heroin self-administration; both followed by extinction of responding. Methyllycaconitine or saline was given prior to reinstatement of drug-primed conditioned place preference, or drug-prime plus cue-induced reinstatement of intravenous self-administration, using two protocols: without delivery of heroin in response to lever pressing to model heroin-seeking, or with heroin self-administration, using fixed and progressive ratio reward schedules, to model relapse.Results:Methyllycaconitine had no effect on acquisition of heroin conditioned place preference or lever-pressing for food rewards. Methyllycaconitine blocked reinstatement of heroin-primed conditioned place preference. Methyllycaconitine did not prevent drug-prime plus cue-induced reinstatement of heroin-seeking, reinstatement of heroin self-administration, or diminish the reinforcing effect of heroin.Conclusions:The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, prevented reinstatement of the opioid conditioned place preference, consistent with a role for α7 nicotinic acetylcholine receptors in the retrieval of associative memories of drug liking. The lack of effect of methyllycaconitine in heroin-dependent rats in two intravenous self-administration models suggests that α7 nicotinic acetylcholine receptors do not play a role in later stages of heroin abuse.

Highlights

Drug addiction is defined as a chronic relapsing disorder (Koob, 2020; Koob and Volkow, 2016)
Administration of MLA prior to heroin conditioning had no effect on the acquisition of heroin conditioned place preference (CPP): both control and MLA-treated rats readily acquired heroin CPP (Figure 1(a))
We have demonstrated that MLA selectively abolished reinstatement of CPP for the more reinforcing morphine analogue, heroin, indicating a consistent role for α7 nicotinic acetylcholine receptors (nAChRs) in the reinstatement of place preference for opioid drugs

Summary

Introduction

Drug addiction is defined as a chronic relapsing disorder (Koob, 2020; Koob and Volkow, 2016). Noteworthy is the current escalation of addiction to opioid drugs worldwide. This has been attributed to over-prescription of painkillers and increased availability of illicit synthetic opioids: heroin and the vastly more dangerous fentanyl (Pergolizzi et al, 2018). Relapse rates to first reuse are approximately 60% after 3 months and 80% after 12 months of abstinence (Bart, 2012; Dong et al, 2017). Major triggers for relapse are stress, drug-associated cues and re-exposure to drugs (Perry et al, 2014; Shalev et al, 2002), and susceptibility persists despite long periods of abstinence (Bart, 2012). Understanding the molecular mechanisms underlying the relapse in opioid addiction will inform the development of more efficacious treatments

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