Differential taurine responsiveness to ethanol in high- and low-alcohol sensitive rats: a brain microdialysis study

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Abstract

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions. However, these studies led to conflicting results, suggesting that individual differences between rat strains and lines may play an important role. In the present study, high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats were used to investigate the possible relationship between ethanol sensitivity and the concentrations of extracellular amino acids in the nucleus accumbens. Several groups of HAS and LAS rats were injected with either saline or ethanol (1.0, 2.0 or 3.0 g/kg, i.p.) and the concentrations of amino acids in the nucleus accumbens microdialysates were assayed by electrochemical detection. Acute ethanol induced a dose-dependent increase in extracellular taurine concentrations. However, this increase was significantly reduced at 2.0 and 3.0 g/kg ethanol in HAS rats relative to LAS rats. Since the biological functions of taurine suggest its implication in the reduction of ethanol adverse effects, a higher increase in taurine concentrations may contribute to the lower ethanol sensitivity of LAS rats. Although 2.0 and 3.0 g/kg ethanol did not affect extracellular glutamate concentrations, a significant increase in glutamate was observed after 1.0 g/kg ethanol to HAS rats but not to LAS rats. Such an effect remains unexplained but suggests that discrepancies between the results of previous microdialysate studies may be related to differences in the ethanol sensitivities of various rat strains.

Introduction

Ethanol, one of the most abused drugs, exerts its action by affecting multiple targets in the central nervous system. It has been shown to interact with almost all identified neurotransmitter systems (see review in Deitrich and Erwin, 1996), although its effects on excitatory and inhibitory amino acid neurotransmissions are particularly important in the mediation of its behavioral effects. Indeed, its positive modulatory action on γ-aminobutyric acid (GABAA) receptors and its inhibitory effects on glutamatergic NMDA receptors have been demonstrated up to the molecular level Grobin et al., 1998, Woodward, 2000. While ethanol's effects on these receptors were extensively studied, ethanol also affects amino acid neurotransmission by altering directly or indirectly the brain extracellular concentrations of these amino acids.

Several in vivo microdialysis studies investigated the effects of an acute ethanol administration on extracellular glutamate concentrations in various rat brain regions, but these experiments led to conflicting results. While the majority of these studies failed to show any effect of ethanol administration on glutamate microdialysate contents Dahchour et al., 1994, Dahchour et al., 1996, Selim and Bradberry, 1996, Quertemont et al., 1998a, Quertemont et al., 1999, Quertemont et al., 2000, high ethanol doses were found to inhibit the release of glutamate in several other studies Shimizu et al., 1998, Yan et al., 1998. In a particular study, ethanol was also shown to induce a biphasic effect on extracellular glutamate concentrations (Moghaddam and Bolinao, 1994). At 0.5 g/kg, ethanol increased the extracellular concentrations of glutamate within the nucleus accumbens and the hippocambus, while ethanol doses higher than 1.0 g/kg reduced extracellular glutamate concentrations. Although these conflicting results remain unresolved, these differences in ethanol-induced changes in extracellular glutamate concentrations could be related to differential sensitivities of various rat brain regions and/or to differences between strains of rats.

While there is no clear evidence that ethanol alters extracellular γ-aminobutyric acid (GABA) concentrations, recent studies show that ethanol increases the release of taurine, another inhibitory amino acid, in various rat brain regions Dahchour et al., 1994, Dahchour et al., 1996, Quertemont et al., 1999, Quertemont et al., 2000. Although taurine release after ethanol administration seems to be part of an osmoregulatory process (Quertemont et al., 2001), the effects of the released taurine might be greater than the sole regulation of cell volume. Indeed, taurine has been shown to exert a neuromodulatory action by inhibiting neuronal cell excitability Billard, 1990, Wang et al., 1998. Although a specific taurine receptor has not been identified in the brain, there is evidence that taurine modulates the activity of the GABA–benzodiazepine receptor complex Bureau and Olsen, 1991, Malminen and Kontro, 1987. Therefore, the increase of brain extracellular taurine concentrations after ethanol administration may contribute to the neurochemical and behavioral effects of ethanol. In agreement with this hypothesis, taurine administration was shown to alter several pharmacological and behavioral effects of ethanol Aragon et al., 1992, Aragon and Amit, 1993, Boggan et al., 1978, Ferko, 1987, McBroom et al., 1986, Messiha, 1979. Particularly, taurine modulates ethanol-reinforcing and aversive effects (Quertemont et al., 1998b), suggesting a possible implication of taurine in ethanol consumption. A previous microdialysis study also shows that the magnitude and duration of ethanol-induced taurine release is related to genetic differences in ethanol preference and aversion (Quertemont et al., 2000). Sardinian ethanol-preferring rats genetically selected for ethanol preference showed a reduced ethanol-induced taurine release in comparison to ethanol nonpreferring rats. However, the Sardinian ethanol-preferring and nonpreferring rats that were used in this later study, display differential sensitivities to ethanol in addition to their differences in ethanol preference (Colombo et al., 2000). Therefore, it remains uncertain whether ethanol-induced taurine release is primarily related to either ethanol preference or sensitivity.

In the present study, high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats were used to test whether the effects of acute ethanol on brain extracellular concentrations of both glutamate and taurine might be related to genetic differences in ethanol sensitivities. HAS and LAS rats from the University of Colorado Health Sciences Center were genetically selected according to their differential sensitivities to the hypnotic effects of acute ethanol. Indeed, the administration of high ethanol doses induces a significantly longer sleep time in HAS rats than in LAS rats Hansen and Spuhler, 1984, Draski et al., 1992. In the present experiment, an in vivo brain microdialysis was performed in the nucleus accumbens of nonanaesthetized HAS and LAS rats and a range of acute ethanol doses (1.0, 2.0 and 3.0 g/kg) were tested. The nucleus accumbens was chosen for two reasons. Firstly, biphasic effects of ethanol on glutamate concentrations were reported in a previous microdialysis experiment within the nucleus accumbens (Moghaddam and Bolinao, 1994). Secondly, although increases in extracellular taurine concentrations after acute ethanol injections were shown in various rat brain regions (Dahchour and De Witte, 2000), this ethanol effect was mainly studied within the nucleus accumbens Dahchour et al., 1994, Dahchour et al., 1996, Dahchour et al., 2000, Quertemont et al., 2000, Quertemont et al., 2001, allowing reliable comparisons with other rat lines and strains.

Section snippets

Animals

From two replicated lines, 28 HAS and 28 LAS male rats, weighing 250–300 g at the time of the study, were randomly divided into four groups of seven rats from each line. All animals were housed in standard individual plastic cages in a temperature- and light-controlled environment (light/dark cycle: 12 h light:12 h dark) with food and water available ad libitum.

All experiments and procedures were carried out according to the European Communities Council Directive (86/609/EEC) for care and use

Blood ethanol concentrations

After i.p. 2.0 g/kg ethanol injections, there was a rapid increase in blood ethanol concentration that reached a maximal level between 40 and 80 min (Fig. 1). The two-way ANOVA indicated no significant differences (P>0.05) with regard to absorption, redistribution and elimination phases of ethanol metabolism between HAS and LAS rats throughout the 240-min experimental period.

Basal amino acid concentrations

Similar mean basal concentrations of alanine, arginine, aspartate, glutamate and taurine were found in the nucleus

Discussion

The results of the present study confirm the effects of acute ethanol on brain extracellular taurine concentrations that were reported in previous microdialysis experiments Dahchour et al., 1994, Dahchour et al., 1996, Quertemont et al., 1999, Quertemont et al., 2000. Acute ethanol at high doses induced an immediate and significant increase in extracellular taurine concentrations from various rat brain regions. This effect required ethanol doses of at least 1.0 g/kg. Indeed, smaller ethanol

Acknowledgements

This work was supported by the Fonds de la Recherche Scientifique et Médicale (1997–2001), the Belgian National Funds for Scientific Research (to Etienne Quertemont), l'Institut de Recherches Economiques sur les Boissons (IREB) and sponsored by LIPHA. The authors wish to thank Dr. Françoise Beaugé for providing the rats.

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