Motivational memory: role of nicotinic receptors in synaptic plasticity

Abstract

Drug addiction is a chronically relapsing disorder characterised by compulsive and uncontrollable drug consumption despite negative consequences. It is considered that in addiction, associative memories are formed, which trigger cravings and prompt relapse during abstinence, which is the largest unmet need of current addiction treatments. Nicotinic acetylcholine receptors (nAChRs) have been implicated in modulating addiction behaviours with drugs of abuse other than nicotine, and studies have provided evidence for a role of α7nAChRs in a morphine reward-based learning paradigm, conditioned place preference (CPP). The aim of this thesis was to characterise the role of α7nAChRs in motivational learning using a more potent opioid, heroin. The selective α7nAChR antagonist methyllycaconitine (MLA) was used to determine if these receptors contribute to the rewarding effects of heroin, the acquisition or the reinstatement of heroin CPP and heroin intravenous self-administration (IVSA). In 6-7 week old male Wistar rats, MLA had no effect on the primary rewarding effects of heroin in either CPP or IVSA experiments. When administered prior to heroin-primed reinstatement of CPP, MLA significantly inhibited reinstatement, demonstrating a selective effect of α7nAChRs on the reinstatement of CPP. Its effects on the heroin- and cue-primed reinstatement of IVSA were however inconclusive due to large variability. The molecular mechanisms of this effect were investigated by immunohistochemistry in brain slices of rats treated with either saline or MLA prior to heroin-primed reinstatement of CPP. AMPA GluA1 and phosphorylated GluA1 subunits were quantified by near-infrared scanning or confocal microscopy but no changes were detected due to methodological issues. The possible mechanistic actions of α7nAChRs in the relevant brain circuits are discussed.

Date of Award	1 May 2019
Original language	English
Awarding Institution	University of Bath
Sponsors	RenaSci Limited
Supervisor	Sue Wonnacott (Supervisor), Chris Bailey (Supervisor) & David Heal (Supervisor)