Abstract
Chronic ethanol consumption causes structural and functional reorganization in the hippocampus and induces alterations in the gene expression of gamma-aminobutyric acid type A receptors (GABAARs). Distinct forced intermittent exposure models have been used previously to investigate changes in GABAAR expression, with contrasting results. Here, we used repeated cycles of a Chronic Intermittent Ethanol paradigm to examine the relationship between voluntary, dependence-associated ethanol consumption, and GABAAR gene expression in mouse hippocampus. Adult male C57BL/6J mice were exposed to four 16-h ethanol vapor (or air) cycles in inhalation chambers alternated with limited-access two-bottle choice between ethanol (15%) and water consumption. The mice exposed to ethanol vapor showed significant increases in ethanol consumption compared to their air-matched controls. GABAAR alpha4 and delta subunit gene expression were measured by qRT-PCR at different stages. There were significant changes in GABAAR delta subunit transcript levels at different time points in ethanol-vapor exposed mice, while the alpha4 subunit levels remained unchanged. Correlated concurrent blood ethanol concentrations suggested that GABAAR delta subunit mRNA levels fluctuate depending on ethanol intoxication, dependence, and withdrawal state. Using a vapor-based Chronic Intermittent Ethanol procedure with combined two-bottle choice consumption, we corroborated previous evidences showing that discontinuous ethanol exposure affects GABAAR delta subunit expression but we did not observe changes in alpha4 subunit. These findings indicate that hippocampal GABAAR delta subunit expression changes transiently over the course of a Chronic Intermittent Ethanol paradigm associated with voluntary intake, in response to ethanol-mediated disturbance of GABAergic neurotransmission.
Highlights
Prolonged excessive ethanol (EtOH) consumption can lead to increased risk of dependence
gamma-aminobutyric acid type A receptors (GABAARs) gene expression is influenced by physiological processes, environmental stimuli, and drugs (Fénelon and Herbison, 1996; Holt et al, 1996; Concas et al, 1998; Smith et al, 1998b; Sanna et al, 2003; Follesa et al, 2004; Biggio et al, 2009; Whissell et al, 2015), and chronic EtOH exposure and withdrawal induce a shift in excitatory/inhibitory tone, with decreased GABAergic inhibition (Kumar et al, 2009)
The baseline intake was similar for both groups (2.49 ± 0.21 Chronic Intermittent EtOH (CIE); 2.76 ± 0.19 air-matched control mice (Air); average 2.63 ± 0.14 g/kg) and drinking in the Air mice remained relatively unchanged, the average EtOH consumption was higher in mice subjected to forced EtOH vapor exposure, reaching ∼4.5 g/kg in the IV cycle (Figure 2A)
Summary
Prolonged excessive ethanol (EtOH) consumption can lead to increased risk of dependence. The subtypes configured with α4/α6 and δ subunits are located exclusively at extrasynaptic sites, where their continuous activation elicits tonic GABAergic inhibition (Farrant and Nusser, 2005; Glykys et al, 2008; Brickley and Mody, 2012) Such extrasynaptic GABAAR subtypes (and α4 and δ subunits) are expressed preferentially in the dentate gyrus of the hippocampus, thalamus, and cerebellar granule cells (Semyanov et al, 2004), with lower levels in the cortex, striatum, CA1 region, and other brain areas (Pirker et al, 2000). Their distinctive properties include a higher affinity for GABA (Saxena and Macdonald, 1996; Brown et al, 2002), higher sensitivity to neuroactive steroids (Adkins et al, 2001; Brown et al, 2002; Wohlfarth et al, 2002; Mody, 2008; Sarkar et al, 2011), and controversially, to acute EtOH (Sundstrom-Poromaa et al, 2002; Wallner et al, 2003) when compared to other GABAAR subtypes
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