GABA_A receptor subtype involvement in addictive behaviour

Abstract

GABA A receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarize the evidence that variations in genes encoding GABA A receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GABA A receptor. In addition to outlining the evidence for the involvement of specific subtypes in addiction, we summarize the particular contributions of these isoforms in control over the functioning of brain circuits, especially the mesolimbic system, and make a first attempt to bring together evidence from several fields to understanding potential involvement of GABA A receptor subtypes in addictive behaviour. While the weight of the published literature is on alcohol dependency, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour.Keywords: Alcohol, animal model, benzodiazepine, conduct disorder, electrophysiology, gene association, gene knockout, impulsivity, nucleus accumbens, psychostimulant, reward Received 31 May 2016, revised 19 July 2016, accepted for publication 15 August 2016Both human and animal studies have implicated GABA A receptors in addiction processes. This article sets out to review the evidence for GABA A receptor involvement in relation to alcoholism and addiction to other drugs of abuse. It will begin with a summary of the structure and function of GABA A receptors and their subtype diversity, before reviewing the human and animal literature providing genetic and behavioural evidence for the role of GABA A receptors in addictive behaviour. Finally, we will attempt to integrate these data into our understanding of addiction processes, and their underlying neurobiology. While the review concerns itself broadly with GABAergic systems and addictive behaviour, the weight of the published literature is on alcohol dependency. Nevertheless, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour.

Drug addictions: new insight into causes, comorbidity and potential treatments

“…Inhibitory gamma-aminobutyric acid (GABA)ergic neurotransmission is Yin to the excitatory glutamatergic Yang of brain signaling. Like glutamate and the NMDA receptor, the GABA system is highly sensitive to alcohol and other drugs of abuse, as discussed in a comprehensive review by Stephens et al (2016). The authors introduce a preclinical literature that has aimed to dissect the relative functional roles of GABA A receptors with differing subunit compositions and relate this to work in humans that identifies a significant genetic association between various subunits (e.g.…”

Endogenous neurosteroids influence synaptic GABAA receptors during postnatal development

“…In common with thalamus and cortex, it can synthesise GABA A R‐active neurosteroids (unpublished observations ‐ Mitchell SJ, Maguire EP, Belelli D, Lambert JJ). Furthermore, we find that adult mice previously exposed to ELS, exhibit altered accumbal GABA A R neurotransmission and an abnormal response to cocaine (ie, an altered locomotor sensitisation), a behaviour that recapitulates in rodents aspects of drug addiction …”

“…Furthermore, we find that adult mice previously exposed to ELS, exhibit altered accumbal GABA A R neurotransmission and an abnormal response to cocaine (ie, an altered locomotor sensitisation), a behaviour that recapitulates in rodents aspects of drug addiction. 140 Schizophrenia is negatively influenced by early-life adversity. [141][142][143] The findings by Grobin et al, 115,116 as discussed above, suggest a possible link between early neurosteroid dysregulation and an abnormal developmental pattern for prefrontal cortex, a region implicated in schizophrenia.…”

Preserved expressive language as a phenotypic determinant of Mosaic Angelman Syndrome

“…The other genes in the distal chromosome 15q11.2‐q13 region include gamma aminobutyric acid (GABA) receptor subunits GABRB3, GABRA5 , and GABRG3 , which are not imprinted. Alterations in the GABAergic systems are associated with hunger (Turenius et al, ), anxiety (Hodges et al, ), OC symptoms, and addiction (Stephens, King, Lambert, Belelli, & Duka, ). While hypoactivity may contribute to obesity in PWS (Dhar et al, ), nearly 60% of our patients were reported to be hyperactive and perhaps this sheds some light on differences in metabolic phenotype in AS compared to PWS.…”