Ethanol-enhanced GABA release: a focus on G protein-coupled receptors

Abstract

While research on the actions of ethanol at the GABAergic synapse has focused on postsynaptic mechanisms, recent data have demonstrated that ethanol also facilitates GABA release from presynaptic terminals in many, but not all, brain regions. The ability of ethanol to increase GABA release can be regulated by different G protein-coupled receptors (GPCRs), such as the cannabinoid-1 receptor, corticotropin-releasing factor 1 receptor, GABA(B) receptor, and the 5-hydroxytryptamine 2C receptor. The intracellular messengers linked to these GPCRs, including the calcium that is released from internal stores, also play a role in ethanol-enhanced GABA release. Hypotheses are proposed to explain how ethanol interacts with the GPCR pathways to increase GABA release and how this interaction contributes to the brain region specificity of ethanol-enhanced GABA release. Defining the mechanism of ethanol-facilitated GABA release will further our understanding of the GABAergic profile of ethanol and increase our knowledge of how GABAergic neurotransmission may contribute to the intoxicating effects of alcohol and to alcohol dependence.

Fig. 1

Ethanol increases vesicular release of GABA. A: A trace from a representative neuron illustrating the effect of ethanol (100mM) on mIPSC frequency. B: Ethanol significantly increased mIPSC frequency compared to control and washout [*p<.05; repeated measures ANOVA; F(2,42)=18.3]. The mIPSC frequency values for the control and washout groups were not significantly different. C: Incubating the slice with bafilomycin A₁ (baf A₁), which eliminates the pH and electrical gradients necessary for GABA transporters to fill the vesicles (Maycox et al., 1990), greatly reduced mIPSC frequency. In the presence of bafilomycin A₁, 100 mM ethanol did not significantly increase mIPSC frequency compared to control. D: Ethanol (100 mM) significantly increased mIPSC frequency (see B) in contrast to weak and non-significant effects on mIPSC fast decay time (τ-fast), slow decay time (τ-slow) and amplitude. Overall, these results support that the ethanol-induced increase in mIPSC frequency should be interpreted as an increase in spontaneous GABA release from the presynaptic terminal. This figure was reproduced from Kelm et al. (2010).

Fig. 2

Ethanol, GABAergic neurotransmission, and GPCRs. Ethanol has been shown to act directly at the postsynaptic GABA_A receptor, but ethanol can also increase the amount of GABA released from the presynaptic terminal. While the mechanism mediating this ethanol effect is not fully understood, evidence suggests that the GPCRs and their respective pathways are involved. It is unlikely that ethanol is binding directly to the GPCR and instead could be acting upstream of the receptor by increasing the amount of ligand reaching the receptor or changing the receptor properties. Ethanol could also interact directly with one of the intracellular messengers (see the text for a detailed description of the GPCR pathways).