The role of alpha7 nicotinic receptors in reinstatement of drug-induced conditioned place preference

Abstract

The cholinergic system in the central nervous system is profoundly implicated in cognition, learning and memory. The ventral hippocampus (vHIP) plays a key role in associative memory, in which acetylcholine (ACh) contributes to modulating neurotransmission and synaptic plasticity. Data from our lab have previously shown that inhibition of alpha7 nicotinic acetylcholine receptors (α7nAChRs) in vHIP via the selective antagonist methyllycaconitine (MLA) specifically attenuated morphine induced reinstatement in a drug-seeking model. However, the specific action by which α7nAChRs regulate drug-related memories in vHIP is poorly understood. The aim of this work was to understand how α7nAChRs in vHIP modulate heroin- and cocaine-induced reinstatement using conditioned place preference (CPP), a Pavlovian paradigm of drug-seeking. 7-9 week old C57BL/6J male mice underwent CPP using either heroin or cocaine as the rewarding drug. Following acquisition and extinction, mice were pre-treated with either saline or MLA (4 mg/kg) prior to heroin- or cocaine-induced CPP reinstatement. MLA inhibited reinstatement of heroin CPP, but not cocaine CPP. The mechanisms of this effect were explored via immunofluorescence for c-Fos expression, a marker of neuronal activation involved in synaptic modifications. After reinstatement of heroin CPP, MLA significantly decreased c-Fos expression in vHIP but not in dorsal hippocampus (dHIP). Subsequently, patch-clamp electrophysiological experiments aimed to explore how α7nAChRs modulate the hippocampal network revealed that α7nAChRs are post synaptically located in both vHIP and dHIP of naïve mice. Moreover, 8-9 weeks old c-Fos-GFP mice, expressing GFP fluorescent protein in c-Fos neurons, underwent heroin-CPP, and electrophysiological experiments were performed to explore mechanisms of synaptic plasticity after heroin-primed reinstatement and how MLA could affect those mechanisms. Finally, a retrograde tracing experiment was performed to understand how the projecting areas of the vHIP are involved in heroin induced reinstatement, by performing brain infusions of retrograde tracers and subsequent co-labelling with c-Fos neurons, defining the major target areas of the vHIP. This thesis demonstrates that α7nAChRs modulate heroin-associated memories selectively in vHIP, where those receptors are post-synaptically located.

Date of Award	2 Nov 2022
Original language	English
Awarding Institution	University of Bath
Sponsors	DevelRx Ltd
Supervisor	Chris Bailey (Supervisor) & Sue Wonnacott (Supervisor)