Central effects of acamprosate: Part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats

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Abstract

One of the known behavioral actions of acamprosate is to decrease hypermotility during alcohol withdrawal. However, the mechanism of this effect remains unclear. In this study, the concentrations of excitatory and inhibitory amino acids were assayed by the microdialysis technique with OPA/BME precolumn derivatization and electrochemical detection in the nucleus accumbens of male Wistar rats which were either alcoholized by ethanol inhalation or simultaneously alcoholized and treated orally by acamprosate (400 mg/kg/day) for 4 weeks. Without treatment, extracellular glutamate increased during the withdrawal phase, while other amino acids tested (aspartate, arginine, taurine, alanine and GABA) remained stable. In contrast, the alcoholized rats treated with acamprosate failed to present the increase in glutamate during ethanol withdrawal, while other amino acids tested also remained stable. The observed glutamate increase could be responsible for the hyperexcitability observed during episodes of ethanol withdrawal. These results suggest that acamprosate is able to reduce the ethanol withdrawal syndrome by reducing the concentration of glutamate in the nucleus accumbens.

Introduction

Although the mechanisms underlying the neuropathology observed in alcohol abusers remains largely unclear, numerous studies have shown that glutamate, the major excitatory amino acid neurotransmitter, is implicated in both hyperexcitability and seizure as observed during ethanol withdrawal in vitro (Iorio et al., 1993, Ruhe and Littleton, 1994, Hoffman, 1995) and in vivo (Hunt, 1993, Rossetti and Carboni, 1995).

Since activation of glutamatergic transmission in the central nervous system is related to activation of voltage operated calcium channels (VOCC), early investigators were interested in the effect of ethanol on these channels (Harris and Hood, 1980, Leslie et al., 1983, Messing et al., 1986, Skattebol and Rabin, 1987). However, in contrast, chronic exposure to ethanol up-regulates the density of these voltage-operated calcium channels as a consequence of tolerance to the inhibitory effect of ethanol (Messing et al., 1986, Dolin et al., 1987, Greenberg et al., 1987, Skattebol and Rabin, 1987, Dolin and Little, 1989, Marks et al., 1989, Whittington et al., 1991) and calcium channel antagonists are able to diminish the alcohol withdrawal syndrome (Little et al., 1986, Koppi et al., 1987, Littleton et al., 1990, Whittington et al., 1991, Whittington et al., 1992, Colombo et al., 1995, Shibata et al., 1995).

Acamprosate (calcium acetyl homotaurinate) has been proposed to prevent relapse in weaned alcoholics (Lhuintre et al., 1985, Tran et al., 1990, Ladewig et al., 1993) and as an anti-craving drug (Littleton, 1995, Littleton et al., 1996). However, the precise function and mechanism of action of acamprosate remain unclear. The aim of the present study was to investigate the effect of chronic acamprosate treatment during chronic intoxication by ethanol on the extracellular changes in neuroexcitatory and neuroinhibitory amino acids within the nucleus accumbens (NAC) of freely moving male rats during ethanol withdrawal.

Section snippets

Animals and surgery

A total of 14 male Wistar rats weighing 250–300 g were individually housed in isolated plastic chambers (160×60×60 cm) in a temperature and light controlled environment (light/darkness cycle: 12 h light/12 h dark cycle) and maintained in an alcohol-containing atmosphere. The rats were either alcoholized by ethanol inhalation (n=7) or simultaneously alcoholized by ethanol inhalation and treated by acamprosate (per os 400 mg/kg/day) (n=7) for a period of 4 weeks. Alcoholization was attained by

Results

Measurements were made of the mean blood-alcohol levels attained in rats at the end of the pulmonary alcohol exposure period and at a time point 12 h later. The blood-alcohol level decreased by approximately 50% (1.90 g/l±0.4–0.96 g/l±0.11) between these two time points.

Fig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 show the time evolution of extracellular concentrations of amino acids measured by microdialysis. In non-treated alcoholized rats, extracellular glutamate significantly increased up to three

Discussion

The NAC, which receives direct glutamatergic connections from the frontal cortex and hippocampus, plays an important role in mediating the reinforcing effects of a large number of drugs including alcohol (Koob and Bloom, 1988, North, 1992).

In the present studies, we have used an in-vivo microdialysis technique to investigate the changes in both excitatory and inhibitory amino acids in the NAC of freely moving male rats during ethanol withdrawal. We also determined whether acamprosate, given

References (55)

  • J. Le Magnen et al.

    Dose-dependent suppression of the high alcohol intake of chronically intoxicated rats by calcium acetyl homotaurinate

    Alcohol

    (1987)
  • J.P. Lhuintre et al.

    Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics

    Lancet

    (1985)
  • Y.P. Li et al.

    Inhibition by taurine of the phosphorylation of specific synaptosomal proteins in the rat cortex: effects of taurine on the stimulation of calcium uptake in mitochondria and inhibition of phosphoinositide turnover

    Brain Research

    (1991)
  • R. Liljequist

    Interaction of taurine and related compounds with GABAergic neurons in the nucleus raphe dorsalis

    Pharmacology, Biochemistry and Behavior

    (1993)
  • H.J. Little et al.

    Calcium channel antagonists decrease the ethanol withdrawal syndrome

    Life Sciences

    (1986)
  • T.E. Robinson et al.

    Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats

    Brain Research

    (1988)
  • Z.L. Rossetti et al.

    Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum

    European Journal of Pharmacology

    (1995)
  • S. Shibata et al.

    Calcium channel blockers improve hypoxia/hypoglycemia-induced impairment of rat hippocampal 2-deoxyglucose uptake in vitro after ethanol withdrawal

    Brain Research

    (1995)
  • A. Skattebol et al.

    Effects of ethanol on 45Ca++ uptake in synaptosomes and in PC 12 cells

    Biochemical Pharmacology

    (1987)
  • M. Williams et al.

    Interaction of taurine and bet-alanine with central nervous system neurotransmitter receptors

    Life Sciences

    (1980)
  • M.L. Zeise et al.

    Acamprosate (calcium acetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of axcitatory amino acids receptors

    European Journal of Pharmacology

    (1993)
  • F. Berton et al.

    The anti-craving agent acamprosate enhances NMDA-mediated EPSPs in rat nucleus accumbens neurons in vitro

    Social Neuroscience Abstracts

    (1995)
  • D.W. Bonhaus et al.

    The interaction of taurine and glutamate metabolism in brains of genetically seizure susceptible and seizure resistant rats

    Proceedings of the Western Pharmacological Society

    (1985)
  • G. Colombo et al.

    Effect of the calcium channel antagonist darodipine on ethanol withdrawal in rats

    Alcohol and Alcoholism

    (1995)
  • A. Dahchour et al.

    Ethanol and acamprosate increase the extracellular taurine in the nucleus accumbens: a microdialysis study

    Alcohol and Alcoholism

    (1995)
  • S. Dolin et al.

    Are changes in neuronal calcium channels involved in ethanol tolerance?

    Journal of Pharmacology and Experimental Therapeutics

    (1989)
  • M. Gewiss et al.

    Acamprosate and diazepam differentially modulate alcohol-induced behavioral and cortical alterations in rats following chronic inhalation of ethanol vapour

    Alcohol and Alcoholism

    (1991)
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