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Treatments of Alcoholism - from
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system by differentially interfering with a number of neurotransmitter systems.
However, the mechanisms by which ethanol produces many of its effects on the
central nervous system are not well understood. The rationale of this work was
intended to assess changes in excitatory and inhibitory amino acid neurotransmitters.
These changes were assayed within specific brain regions i.e. nucleus accumbens,
hippocampus and frontal cortex of freely moving Wistar rats, after ethanol treatment
using the in vivo microdialysis technique associated with electrochemical detection.
The earliest studies have evidently demonstrated that sulphonated amino acid taurine
content of nucleus accumbens (1), hippocampus (unpublished data), frontal cortex
(unpublished data), and amygdala (3) microdialysate significantly increased 20-40
minutes after an acute injection of 1, 2, and 3 g/kg ethanol to naive rats. Likewise, in
rats, which received chronic ethanol injections of 1, 2, and 3 g/kg body weight for 1, 2
and 3 weeks duration prior to the acute ethanol injections, a comparable increase in
nucleus accumbens taurine microdialysate content was assayed (2). No significant
changes were observed in either glutamate or GABA microdialysate contents in any
of these studies. In rats, which were physically dependent upon alcohol (the ethanol
dependence was induced by vapour inhalation for 4 weeks), the basal concentrations
of both arginine and GABA were significantly decreased (5). However, during the
first 12h-withdrawal phase only glutamate significantly increased, commencing 5h
after withdrawal (4). To ascertain whether taurine and ethanol interact with other
amino acids during ethanol withdrawal, two other groups of ethanol dependent rats
were treated, with either taurine (45 mg/kg) or ethanol (2 g/kg) five hours after the
commencement of withdrawal. Ethanol administration significantly increased taurine
microdialysate content in the nucleus accumbens but failed to modify the
concentration of either glutamate or other amino acids during the first 12h of
withdrawal (8). In contrast, taurine treatment significantly blocked the glutamate
with an increase in glutamate release in the nucleus accumbens (4) and hippocampus
(6), further investigations assessed whether repeated cycles of chronic ethanol
intoxication followed by withdrawal periods, would alter excitatory amino acids in the
hippocampus, of male rats. In these studies, during the third cycle of ethanol
withdrawal the increase in both glutamate and aspartate was much higher than during
the first episode of withdrawal (9). To elucidate the mechanisms by which
acamprosate may achieve its therapeutic effects, two groups of rats were chronically
alcoholized by ethanol inhalation for four weeks and simultaneously administered
acamprosate (400 mg/kg/day) or not for the duration of this period. Acamprosate
reduced both the hypermotility (5) and the increased glutamate in the microdialysate
of the nucleus accumbens (4), which occurred during the first 12h of ethanol
withdrawal in the non supplemented group. The basal concentration of both taurine
and GABA increased significantly in acamprosate treated group (5). The effect of
acamprosate on excitatory amino acids was also assessed during repeated ethanol
withdrawal of 24h each (9). During the first cycle of ethanol withdrawal, the
administration of acamprosate (400 mg, i.p.) two hours after the commencement of
ethanol withdrawal decreases both glutamate and aspartate microdialysate levels by
comparison to acamprosate untreated group. During the third withdrawal period,
further increases were seen in both glutamate and aspartate microdialysate levels in
acamprosate untreated group. Acamprosate administration reduces significantly the
glutamate level, while aspartate levels were steady increased during the last 12h of
withdrawal in the two groups. Interestingly, taurine level was significantly increased
after acamprosate administration during the third withdrawal period by comparison to
acamprosate untreated group. Overall, these results reviewed in (7) demonstrate
clearly that ethanol alters differentially excitatory and inhibitory neurotransmitters by
varying degrees, which is dependent upon a variety of factors, which include ethanol
treatment, and the brain regions investigated. Such alterations may play a role in
development of tolerance and dependence which results in the hyperexcitability
observed during ethanol withdrawal. Moreover, acamprosate, which is a new
therapeutic drug used to treat alcoholism, is able to reduce the hypermotility and
excitatory amino acids during the ethanol withdrawal. This could be explained by the
possibility of acamprosate action directly at the glutamate receptors and in part by
increasing taurine and GABA levels in specific brain regions and acamprosate
increased these inhibitory amino acid levels would pronounce the protective
mechanism against the neurotoxicity and even the death (10) induced by excitatory
amino acids particularly glutamate.
DAHCHOUR A., QUERTEMONT E. and DE WITTE P. Acute ethanol increases taurine but
neither glutamate nor GABA in the nucleus accumbens of male rats: a microdialysis study.
Alcohol and Alcoholism, 29: 485-487, 1994.
DAHCHOUR A., QUERTEMONT E., and DE WITTE P. Taurine increases in the nucleus
accumbens microdialysate after acute ethanol administration to naive and to chronically
alcoholised rats. Brain Research, 735: 9-19, 1996.
QUERTEMONT E., DAHCHOUR A., WARD R. J. and DE WITTE P. Ethanol induces taurine
release in the amygdala: an in vivo microdialysis study. Addiction Biology, 4: 47-54, 1999.
DAHCHOUR A., BOLO N., NEDELEC J. F., DE WITTE P., DURBIN P. and MACHER J. P.
Central effect of acamprosate: Part1 acamprosate blocks the glutamate increase in the nucleus
accumbens microdialysate during ethanol withdrawn rats. Psychiatry Research Neuroimaging.
82: 107-114, 1998.