GABRB1 Single Nucleotide Polymorphism Associated with Altered Brain Responses (but not Performance) during Measures of Impulsivity and Reward Sensitivity in Human Adolescents

Abstract

Variations in genes encoding several GABAA receptors have been associated with human drug and alcohol abuse. Among these, a number of human studies have suggested an association between GABRB1, the gene encoding GABAA receptor β1 subunits, with Alcohol dependence (AD), both on its own and comorbid with other substance dependence and psychiatric illnesses. In the present study, we hypothesized that the GABRB1 genetically-associated increased risk for developing alcoholism may be associated with impaired behavioral control and altered sensitivity to reward, as a consequence of altered brain function. Exploiting the IMAGEN database (Schumann et al., 2010), we explored in a human adolescent population whether possession of the minor (T) variant of the single nucleotide polymorphism (SNP) rs2044081 is associated with performance of tasks measuring aspects of impulsivity, and reward sensitivity that are implicated in drug and alcohol abuse. Allelic variation did not associate with altered performance in either a stop-signal task (SST), measuring one aspect of impulsivity, or a monetary incentive delay (MID) task assessing reward anticipation. However, increased functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent (BOLD) response in the right hemisphere inferior frontal gyrus (IFG), left hemisphere caudate/insula and left hemisphere inferior temporal gyrus (ITG) during MID performance was higher in the minor (T) allelic group. In contrast, during SST performance, the BOLD response found in the right hemisphere supramarginal gyrus, right hemisphere lingual and left hemisphere inferior parietal gyrus indicated reduced responses in the minor genotype. We suggest that β1-containing GABAA receptors may play a role in excitability of brain regions important in controlling reward-related behavior, which may contribute to susceptibility to addictive behavior.

GABAA receptor subtype involvement in addictive behaviour

“…In contrast, during SST performance, the BOLD response found in the right hemisphere supramarginal gyrus, right hemisphere lingual and left hemisphere inferior parietal gyrus indicated reduced responses in the minor genotype. We suggest that β1‐containing GABA A receptors may play a role in excitability of brain regions important in controlling reward‐related behaviour, which may contribute to susceptibility to addictive behaviour (Duka et al ., in press).…”

Nuclear Respiratory Factor 1 (NRF-1) Controls the Activity Dependent Transcription of the GABA-A Receptor Beta 1 Subunit Gene in Neurons

“…Through linkage studies, GABRB1 has been associated with alcohol dependance (Parsian and Zhang, 1999 ; Sun et al, 1999 ; Zinn-Justin and Abel, 1999 ; Song et al, 2003 ); and more recently, specific mutations in mouse Gabrb1 have been shown to produce increased alcohol consumption that is linked to increased tonic inhibition (Anstee et al, 2013 ). Interestingly, single nucleotide polymorphisms in GABRB1 are also associated with altered brain responses in human adolescents susceptible to addictive behaviors (Duka et al, 2017 ).…”

A quantitative trait variant inGabra2underlies increased methamphetamine stimulant sensitivity

“…variants have been associated with alcohol dependence and co-morbid substance use disorders and altered fMRI BOLD signal in multiple gyri and the caudate/insula during impulsivity and reward sensitivity tasks (Duka et al 2017); thus, GABRB1 is hypothesized to regulate excitability of GABA-A receptors in brain regions underlying reward-related behavior and possibly addiction. Concomitant decreases in Gabrb1 and Gabra2 expression were observed in cortex, striatum, and hippocampus of B6J mice relative to the corrected B6J KI line (Mulligan et al 2019).…”