Abdelkhader Dahchour

Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate.

Ethanol induces alterations in the central nervous system by differentially interfering with a number of neurotransmitter systems, although the mechanisms by which such effects are executed are not well understood. The present review therefore, is designed to ascertain the effect of ethanol on both excitatory and inhibitory amino acid neurotransmitters, as well as the sulphonated amino acid taurine, assayed by the microdialysis technique within specific brain regions of rat during different types of alcohol intoxication, acute and chronic, as well as during the withdrawal period. Such an understanding of these pharmacological actions of ethanol on neurotransmitters is essential in order to provide the impetus for the development of appropriate therapeutic intervention to ameliorate the multitude of neurochemical disorders induced by ethanol. In addition the possible mode of action of a new therapeutic drug for the treatment of alcoholism, acamprosate will be discussed. The first part of this review will be limited to studies of the effect of ethanol on both amino acid neurotransmitters and the sulphonated amino acid taurine, a possible neuromodulator. While, the second part will seek to establish the possible mechanism of action of a new therapeutic drug, acamprosate, which is used to combat the effects of ethanol, particularly during the craving period, as well as maintaining abstinence in weaned alcoholics.

Taurine increases in the nucleus accumbens microdialysate after acute ethanol administration to naive and chronically alcoholised rats

The extracellular changes of amino acids (glutamate, taurine and GABA) in the nucleus accumbens of freely moving rats were estimated using the microdialysis technique following acute and chronic ethanol injections (1, 2, and 3 g/kg body weight). Compared to baseline values, taurine increased by 154% +/- 73%, 142% +/- 40% and 162% +/- 75% 20 min after the acute injection of respectively, 1, 2, and 3 g/kg body weight ethanol, while 40 min after ethanol injection, taurine had increased by 124% +/- 36%, 146% +/- 54% and 168% +/- 98%. No changes in either glutamate or GABA were detected at any time points assayed. In the rats which had received chronic ethanol administration prior to a further acute ethanol injection (1, 2, and 3 g/kg body weight), taurine increased by 138% +/- 73%. 144% +/- 39% and 180% +/- 85% 20 min after the ethanol injection at 40 min post ethanol injection taurine had increased by 134% +/- 44%, 160% +/- 56% and 158% +/- 45%, compared to the basal baseline value. No significant changes were observed in either glutamate or GABA microdialysate content in these chronic studies. The biological role played by taurine after acute ethanol injection in the nucleus accumbens remains unclear but may be associated with a yet, undefined mechanism, in reducing the cytotoxicity of ethanol.

Acetaldehyde-induced changes in the monoamine and amino acid extracellular microdialysate content of the nucleus accumbens

The effect of an acute intraperitoneal (i.p.) injection of acetaldehyde, 20 mg/kg or 100 mg/kg, on the microdialysate content of both amino acids and monoamines was studies in the nucleus accumbens (NA) by a microdialysis technique. Acetaldehyde, ACH, which was detectable at levels of 50-130 mumol/g brain tissue 10 min after injection, evoked a significant decrease in the extracellular microdialysis dopamine content, which was sustained for the period of the study, i.e. 120 min. Homovanillic acid, HVA, decreased significantly when the lower dose of ACH was administered while dihydrophenylacetic acid, DOPAC, showed no significant change with either dose of ACH during the period of the study. Serotonin levels decreased significantly after both doses of acetaldehyde, with significant increases of its major metabolite, hydroxyindolacetic acid, 5-HIAA, with the higher acetaldehyde dose. Taurine increased significantly, only during the first twenty minutes, after both doses of acetaldehyde, although neither of the excitatory amino acids assayed, glutamate and aspartate, nor the inhibitory amino acid, GABA, showed any significant changes. Acetaldehyde clearly evokes significant perturbation in the monoamine content of the NA, such changes being the converse to those reported for monoamines after ethanol administration, which might indicate a negative reinforcement effect.

Ethanol induces taurine release in the amygdala: an in vivo microdialysis study.

The effect of acute IP ethanol injections on the extracellular aspartate, glutamate, taurine and GABA content of the basolateral amygdala microdialysate was investigated in relationship with total brain ethanol. Each acute intraperitoneal injection of ethanol, 0.5, 1.0, 2.0 and 3.0 g/kg body weight, induced an immediate increase in microdialysate taurine; both 0.5 and 1.0 g/kg ethanol evoked an increase during the first 20 minutes following injection which returned to baseline value by 40 minutes, despite the fact that ethanol was detectable in the brain until 60 or 120 minutes, respectively. After either 2.0 or 3.0 g/kg ethanol there was an increase in taurine of gradual intensity which gradually declined to reach baseline values by 100 minutes. In contrast, the ethanol concentration for 2.0 g/kg remained elevated at the end of the 120 minutes; approximately 25 mg ethanol/mg protein. The stimulated release of taurine within the amygdala could participate in the regulation of ethanolinduced changes in osmolarity, since taurine is postulated to act as an osmoregulator in the brain. Taurine could also mediate or interact with ethanol‐induced central nervous system effects, as it exerts a modulatory action on cell excitability and neurotransmitter processes.

Does taurine play an osmolarity role during ethanol intoxication

The transition of life from an aquatic environment to a terrestrial habitat necessitated the evolution of an inert zwitteronic ion with high solubility and low lipophilicity which could move between intraand extra-cellular compartments to maintain cellular volume. Taurine was that compound. With higher evolutionary development a wide number of other biological functions have been assigned to taurine, including calcium homeostasis1, an involvement in the NMDA receptor activity2, as well as a modulator of hypochlorous acid toxicity within leucocytes3. Its role as an osmotic regulator appears to be retained in higher organisms; imposition of an osmotic challenge to animals and certain cell lines5 show an increase in taurine release to the exterior media in order to maintain cellular volume. Alcohol administration, either chronic or acute will have a devastating effect upon extracellular and intracellular compartments by virtue of the fact that ethanol rapidly diffuses across all membranes including the blood brain barrier. This could lead to osmotic disturbances in the brain which could perturb the complex relationship between neurotransmitters and their receptors. The exact role of taurine in the brain remains undefined; it is unlikely to be a neurotransmitter but may modify the action of the excitatory amino acid glutamic acid7. Microdialysis experiments of the hippocampus show that taurine is elevated transitorily after an acute injection of ethanol although