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 Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats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