GABA (Gamma-Aminobutyric acid) [BSA]

Animal studies have established that acute alcohol increases neural inhibition and that frequent intoxication episodes elicit neuroadaptive changes in the excitatory/inhibitory neurotransmission balance. To compensate for the depressant effects of alcohol, neural hyperexcitability develops in alcohol use disorder and is manifested through withdrawal symptoms. It is unclear, however, whether neuroadaptive changes can be observed in young, emerging adults at lower levels of consumption in the absence of withdrawal symptoms. Here, we used an anatomically constrained magnetoencephalography method to assess cortical excitability in two independent sets of experiments. We measured early visual activity (1) in social drinkers during alcohol intoxication versus placebo conditions and (2) in parallel cohorts of sober binge drinkers (BDs) and light drinkers (LDs). Acute alcohol intoxication attenuated early sensory activity in the visual cortex in social drinkers, confirming its inhibitory effects on neurotransmission. In contrast, sober BDs showedgreaterneural responsivity compared with a matched group of LDs. A positive correlation between alcohol consumption and neural activity in BDs is indicative of cortical hyperexcitability associated with hazardous drinking. Furthermore, neural responsivity was positively correlated with alcohol intake in social drinkers whose drinking did not reach binge levels. This study provides novel evidence of compensatory imbalance reflected in the downregulation of inhibitory and upregulation of excitatory signaling associated with binge drinking in young, emerging adults. By contrasting acute effects and a history of BD, these results support the mechanistic model of allostasis. Direct neural measures are sensitive to synaptic currents and could serve as biomarkers of neuroadaptation.

The neurosteroid allopregnanolone (ALLO) causes unconsciousness by allosteric modulation of gamma-aminobutyric acid type A (GABA(A)) receptors, but its actions on the spinal motor networks are unknown. We are therefore testing the hypothesis that ALLO attenuates the action potential firing of spinal interneurons and motoneurons predominantly via enhancing tonic, but not synaptic GABAergic inhibition. We used video microscopy to assess motoneuron-evoked muscle activity in organotypic slice cultures prepared from the spinal cord and muscle tissue. Furthermore, we monitored GABA(A) receptor-mediated currents by performing whole-cell voltage-clamp recordings. We found that ALLO (100 nM) reduced the action potential firing of spinal interneurons by 27% and that of alpha-motoneurons by 33%. The inhibitory effects of the combination of propofol (1 mu M) and ALLO on motoneuron-induced muscle contractions were additive. Moreover, ALLO evoked a tonic, GABA(A) receptor-mediated current (amplitude: 41 pA), without increasing phasic GABAergic transmission. Since we previously showed that at a clinically relevant concentration of 1 mu M propofol enhanced phasic, but not tonic GABAergic inhibition, we conclude that ALLO and propofol target distinct subpopulations of GABA(A) receptors. These findings provide first evidence that the combined application of ALLO and propofol may help to reduce intraoperative movements and undesired side effects that are frequently observed under total intravenous anesthesia.