Effects of Ethanol on GABA_A Receptors in GABAergic and Glutamatergic Presynaptic Nerve Terminals

Abstract

Ethanol (EtOH) has a number of behavioral effects, including intoxication, amnesia, and/or sedation, that are thought to relate to the activation of GABA A receptors. However, GABA A receptors at different cellular locations have different sensitivities to EtOH. The present study used the "synaptic bouton" preparation where we could stimulate nerve endings on mechanically dissociated single rat hippocampal CA1 and CA3 pyramidal neurons and investigate the effects of EtOH on presynaptic and postsynaptic GABA A receptors. Low concentrations of EtOH (10 mM) had no effect on postsynaptic GABA A and glutamate receptors or voltage-dependent Na ϩ and Ca 2ϩ channels. Higher concentrations (Ն100 mM) could significantly inhibit these current responses. EtOH at 10 mM had no direct effect on inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) evoked by focal stimulation of single boutons [evoked IPSCs (eIPSCs) and evoked EPSCs (eEPSCs)]. However, coapplication of 10 mM EtOH with muscimol decreased the amplitude of eIPSCs and eEPSCs and increased their paired-pulse ratio. The effects on eEPSCs were reversed by bicuculline. Coapplication of muscimol and EtOH significantly increased the frequency of spontaneous IPSCs and EPSCs. The EtOH effects on the postsynaptic responses and eEPSCs were similar in neurons from neonatal and mature rats. These results revealed that low concentrations of EtOH can potentiate the activation of presynaptic GABA A receptors to inhibit evoked GABA and glutamate release. These results indicate a high sensitivity of presynaptic GABA A receptor to EtOH, which needs to be accounted for when considering the cellular mechanisms of EtOH's physiological responses.

Inhibition of Excitatory Synaptic Transmission in Hippocampal Neurons by Levetiracetam Involves Zn2+-Dependent GABA Type A Receptor–Mediated Presynaptic Modulation

“…As shown in Fig. 1A, P 1 and P 2 eEPSCs appeared in an all-or-none fashion, as reported previously (Shin et al, 2012a,b;Wakita et al, 2012), with approximately 13.2 6 1.5% (n 5 43 neurons [boutons]) of stimuli producing no responses or response failures.…”

“…All recordings were obtained from the soma of CA3 pyramidal neurons using conventional whole-cell patch-clamp recordings in voltage-clamp mode. Glutamatergic eEPSCs were recorded at a holding potential (V H ) of 265 mV, while voltage-dependent Na 1 channel currents (I Na ) and high-threshold Ca 21 channel currents (I Ba ) were recorded at V H values of 270 mV and 260 mV, respectively (Multiclamp 700B; Molecular Devices, Sunnyvale, CA) (Wakita et al, 2012). All experiments were performed at room temperature (21224°C).…”

“…ATP-Mg was dissolved in the internal solution just before use. Glutamatergic eEPSCs were isolated from GABAergic eIPSCs by recording at a V H of 265 mV, which is close to the Cl 2 equilibrium potential (E Cl ) (Wakita et al, 2012).…”

Increased brain uptake and oxidation of acetate in heavy drinkers

“…Alcohol use is characterized by CNS intoxication symptoms, impaired brain activity, poor motor coordination, and behavioral changes. The impairments in CNS activities are due to alcohol's effect on synthesis, release, and signaling of neuron transmitters, including glutamate, GABA, and other neuron transmitters (1)(2)(3). Alcohol use also affects insulin sensitivity that regulates protein, carbohydrate, and fat metabolism (4).…”

The Detection of a GABAAR β3 Subunit in an Affinity-Purified Preparation of the GABAAR-Associated Cl-/HCO3 --ATPase Isolated from Rat Brain

“…Low concentrations of EtOH (<30 mM) activate and a high concentrations (>200 mM) inhibit the GABA A R function [24,25].…”