Ethanol stimulates gamma-aminobutyric acid receptor-mediated chloride transport in rat brain synaptoneurosomes.

Abstract

The effects of ethanol on Cl-uptake were studied using a cell-free subcellular preparation from brain that contains a y-aminobutyric acid (GABA)/barbiturate receptor-sensitive Cl transport system. In isolated vesicles prepared from rat cerebral cortex, ethanol, at concentrations that are present during acute intoxication (20-50 mM), stimulated 36CI-uptake in a concentration-dependent and biphasic manner. The ethanol-stimulated uptake of 36CI-was markedly inhibited by the GABA antagonists picrotoxin and bicuculline but not by a variety of other neurotransmitter receptor antagonists. The effects of ethanol in stimulating 36CI-uptake in isolated brain vesicles were qualitatively and quantitatively similar to that of pentobarbital. Ethanol also markedly potentiated both muscimol-and pentobarbital-stimulated 36CI-uptake at concentrations below those that directly stimulate Cl-uptake. Under our incubation conditions, ethanol did not release GABA, suggesting that it interacts with the postsynaptic GABA/barbiturate receptor complex. The ability of ethanol to stimulate GABA/barbiturate receptor-mediated Cl-transport may explain many of its pharmacological properties and provides a mechanism for the common psychopharmacological actions of ethanol, barbiturates, and benzodiazepines.Ethanol is one of the oldest and most commonly used of all psychotropic drugs (1). Repeated exposure to ethanol produces both psychological and physical dependence and its abuse potential constitutes a major public health problem (2). The neurochemical mechanism(s) underlying the depressant effects of ethanol on the central nervous system (CNS) is poorly understood (3) despite numerous studies demonstrating effects of ethanol on several neurotransmitter systems (4, 5). Ethanol shares many pharmacologic actions with both barbiturates and benzodiazepines. For example, ethanol, like barbiturates and benzodiazepines, possesses anxiolytic and sedative/hypnotic activity in both laboratory animals (6, 7) and humans (8). Moreover, previous studies have documented the development of behavioral cross-tolerance between ethanol, barbiturates, and benzodiazepines (9, 10). Benzodiazepines and barbiturates, which also show crossdependence with each other, are effective in alleviating the withdrawal symptoms that occur after chronic ethanol administration, suggesting that all three drugs may share a common mechanism of action (11).It is now generally accepted that both benzodiazepines and barbiturates produce their major pharmacological effects by augmenting the actions of the principal inhibitory neurotransmitter of brain, y-aminobutyric acid (GABA) (12)(13)(14)(15) ly associated with the Cl-channel in both rat and mouse brain membranes (25,26). Unfortunately, the concentrations of ethanol used in many of these receptor binding studies exceed those observed during acute intoxication (>30 mM) and are, in fact, many times above the lethal concentration (>100 mM) (27,28).Recently, we have reported the use of the "synaptoneurosome," a subcellular brain pre...

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…For example, it was observed that ethanol enhanced GABAinduced chloride flux in synapto-neurosomes (Suzdak et al, 1986b). Other studies of cultured neurons seemed consistent with ethanol having an action on GABA A receptors at concentrations below 100 mM (Aguayo, 1990;Reynolds and Prasad, 1991;Reynolds et al, 1992; see review by Mihic, 1999).…”

Ethanol potentiates and blocks NMDA‐activated single‐channel currents in rat hippocampal pyramidal cells

“…Suzdak et al [6] showed that 220 mM of EtOH stimulate Cl-uptake via GABA receptor-coupled chloride ion channels in cerebral cortical synaptosomes, but subintoxicating concentrations (I 10 mM) potentiate both muscimol-and pentobarbital-stimulated Cl-uptake. In the present work the range of concentrations of EtOH used was 1.74-174 mM, a relatively low level when compared to the values seen in the literature [6,26]. The effects seen on the NMDA-activated channel currents at such a low concentration may not be due to unspecific effects of EtOH on the membrane lipids themselves.…”

Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol

“…Behavioral and neurochemical evidence suggests that alcohol exerts pharmacological effects remarkably similar to GABA A receptor modulators, including 3␣,5␣-THP (Suzdak et al, 1986b;Grobin et al, 1998). Several ethanol effects are enhanced by the positive GABA A receptor modulators benzodiazepines and barbiturates, but are blocked by GABA A receptor antagonists and inverse agonists (Suzdak et al, 1986a;Nutt and Lister, 1989;Givens and Breese, 1990;Liu and Deitrich, 1998).…”