Nucleus accumbens GABAA receptor-mediated inhibitory transmission: Relevance to early life stress and addiction
type: CreativeWork
description: The nucleus accumbens (NAc) consists primarily of GABAergic neurons, and is an essential integration site within the natural reward-pathway, which is ‘hijacked’ by drugs of abuse. We have previously shown for accumbal medium spiny neurons (MSNs) that α2-subunit containing GABAA receptors (α2-GABAARs), mediate phasic inhibition and that their genetic inactivation (α2-/-) abolishes behavioural sensitisation to cocaine. Recently, linkage association studies in humans revealed a genetic association of GABRA2 haplotypes with cocaine addiction, which was evident only in individuals who had experienced childhood trauma. Collectively, these studies indicate an association of childhood trauma, drug addiction and the GABRA2 haplotype. Here, I have characterised the NAcore MSN GABAARs, identifying two distinct synaptic populations namely α1- and α2-GABAARs. Having established the GABAAR isoforms in control mice I then employed a mouse model of early life stress (ELS) to investigate the impact of early-life adverse experiences on cocaine-induced behaviours and the putative role of NAcore GABAARs in this interaction. An established fragmented maternal care paradigm was implemented to produce ELS. Adult wild type (WT) control mice received a daily i.p injection of cocaine (10 mg/kg) for 10 days, which resulted in behavioural sensitization, manifested as enhanced cocaine-induced increase of locomotor activity c.f. saline-injected controls. In contrast, adult ELS mice did not sensitise to cocaine, but exhibited a significantly increased acute locomotor response to a single cocaine injection (10 mg/kg) c.f. WT control. Interestingly, both features were exhibited by non-stressed α2-/- mice. Whole-cell voltage-clamp recordings of NAc MSNs of adult mice, previously exposed to the ELS paradigm, revealed a significant reduction in the amplitude and frequency of miniature inhibitory post-synaptic currents (mIPSCs) c.f. WT controls. Non-stressed α2-/- mice exhibited similar alterations of …
abstract: The nucleus accumbens (NAc) consists primarily of GABAergic neurons, and is an essential integration site within the natural reward-pathway, which is ‘hijacked’ by drugs of abuse. We have previously shown for accumbal medium spiny neurons (MSNs) that α2-subunit containing GABAA receptors (α2-GABAARs), mediate phasic inhibition and that their genetic inactivation (α2-/-) abolishes behavioural sensitisation to cocaine. Recently, linkage association studies in humans revealed a genetic association of GABRA2 haplotypes with cocaine addiction, which was evident only in individuals who had experienced childhood trauma. Collectively, these studies indicate an association of childhood trauma, drug addiction and the GABRA2 haplotype. Here, I have characterised the NAcore MSN GABAARs, identifying two distinct synaptic populations namely α1- and α2-GABAARs. Having established the GABAAR isoforms in control mice I then employed a mouse model of early life stress (ELS) to investigate the impact of early-life adverse experiences on cocaine-induced behaviours and the putative role of NAcore GABAARs in this interaction. An established fragmented maternal care paradigm was implemented to produce ELS. Adult wild type (WT) control mice received a daily i.p injection of cocaine (10 mg/kg) for 10 days, which resulted in behavioural sensitization, manifested as enhanced cocaine-induced increase of locomotor activity c.f. saline-injected controls. In contrast, adult ELS mice did not sensitise to cocaine, but exhibited a significantly increased acute locomotor response to a single cocaine injection (10 mg/kg) c.f. WT control. Interestingly, both features were exhibited by non-stressed α2-/- mice. Whole-cell voltage-clamp recordings of NAc MSNs of adult mice, previously exposed to the ELS paradigm, revealed a significant reduction in the amplitude and frequency of miniature inhibitory post-synaptic currents (mIPSCs) c.f. WT controls. Non-stressed α2-/- mice exhibited similar alterations of …
author: Mitchell, Scott John
language: eng
keywords: GABAA receptor, Addiction, Early life stress, Neurosteroids
date published: 2016
date modified: 2026-07-24T02:08:19Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee