Frédéric Lallemand

Neuro-inflammation induced in the hippocampus of 'binge drinking' rats may be mediated by elevated extracellular glutamate content

The neuropathological and immune changes induced in the brain by ‘binge drinking’ have been investigated in a rat model. Evidence of neuro‐inflammation was identified in the ‘binge drinking’ rat model of alcohol abuse after 3 weeks of administration of 2 or 3 g/kg ethanol (EtOH), three times per day for two consecutive days, followed by 5 days of abstinence: Firstly, alveolar macrophages, isolated from these animals, showed significant increases in inducible nitric oxide synthase, as assayed by nitrite release, both before and after lipopolysaccaharide stimulation. Secondly, significant numbers of activated microglia were present in the dentate gyrus region of the hippocampus of the ‘binge drinking’ model, after major histocompatibility complex class II staining, by comparison with the control. Microdialysis studies in the ventral hippocampus identified a significant increase in the basal extracellular concentration of glutamate, in both the 2 and 3 g/kg administered ‘binge drinking’ rats. In contrast, no changes in the hippocampal extracellular concentrations, of GABA and taurine, or the dopamine and serotonin metabolites were observed under basal conditions. A further dose of EtOH induced a significant decrease in the concentrations of both 3,4‐dihydroxyphenylacetic acid and 5‐hydroxyindoleacetic acid, whereas glutamate, taurine and GABA levels were unaffected. There was no evidence that EtOH preference was initiated by the ‘binge drinking’ regimen. Our results suggest that the possible toxicity associated with ‘binge drinking’ maybe directed by the elevated glutamate levels, which in turn, activate phagocytic cells to release their inflammatory cytokines and chemokines, ultimately leading to neuro‐inflammation.

Neuroreceptors and ion channels as targets of alcohol

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Kinya Kuriyama. The presentations were (1) Modulation of neuroreceptors and ion channels by alcohol, by T. Narahashi; (2) Inhibition by ethanol of NMDA and AMPA receptor-channels, by P. Illes, K. Wirkner, W. Fischer, K. Mühlberg, P. Scheibler, and C. Allgaier; (3) Effects of ethanol on metabotropic glutamate receptors, by K. Minami; (4) Acute alcohol actions on the 5-HT3 ligand-gated ion channel, by D. Lovinger; (5) Inhibition of NMDA receptors by MK801 attenuates ethanol-induced taurine release from the hippocampus, by F. Lallemand, R.J. Ward, and P. DeWitte; and (6) Effect of ethanol on voltage-operated Ca2+ channels in hepatic stellate cells, by T. Itatsu, Y. Takei, H. Oide, M. Hirose, X. E. Wang, S. Watanabe, M. Tateyama, R. Ochi, and N. Sato.

Decreased release of nitric oxide (NO) by alveolar macrophages after in vivo loading of rats with either iron or ethanol.

Alveolar macrophages were isolated by pulmonary lavage from rats which had been either chronically overloaded with iron by intraperitoneal injections of iron dextran for four weeks, or rendered alcoholic by administration of increasing concentrations of alcohol vapour, also for four weeks. Although the hepatic iron content increased in both groups of animals, only the macrophages isolated from the iron-loaded animals showed a significant increase in iron content (P = < 0.05). Furthermore, in these macrophages there was a significant increase in oxidative tone as demonstrated by a six fold increase in superoxide dismutase activity. In both the iron-loaded and chronically alcoholised macrophages, there was a significant diminution in nitric oxide release after stimulation with lipopolysaccharide and/or interferon-gamma, which impaired the ability of both of these groups of macrophages to inhibit the germination of spores from the fungus Rhizopus, a nitric oxide-dependent process. Such an alteration in nitric oxide release reduces the macrophages microbicidal activity.

Increased cortical activity in binge drinkers during working memory task: a preliminary assessment through a functional magnetic resonance imaging study.

Background Cerebral dysfunction is a common feature of both chronic alcohol abusers and binge drinkers. Here, we aimed to study whether, at equated behavioral performance levels, binge drinkers exhibited increased neural activity while performing simple cognitive tasks. Methods Thirty-two participants (16 binge drinkers and 16 matched controls) were scanned using functional magnetic resonance imaging (fMRI) while performing an n-back working memory task. In the control zero-back (N0) condition, subjects were required to press a button with the right hand when the number “2″ was displayed. In the two-back (N2) condition, subjects had to press a button when the displayed number was identical to the number shown two trials before. Results fMRI analyses revealed higher bilateral activity in the pre-supplementary motor area in binge drinkers than matched controls, even though behavioral performances were similar. Moreover, binge drinkers showed specific positive correlations between the number of alcohol doses consumed per occasion and higher activity in the dorsomedial prefrontal cortex, as well as between the number of drinking occasions per week and higher activity in cerebellum, thalamus and insula while performing the N2 memory task. Conclusions Binge alcohol consumption leads to possible compensatory cerebral changes in binge drinkers that facilitate normal behavioral performance. These changes in cerebral responses may be considered as vulnerability factors for developing adult substance use disorders.

Taurine concentration in the brain and in the plasma following intraperitoneal injections.

Summary.The effect of different taurine doses (0.050, 0.125, 0.250, 0.500 and 1.000 g/kg) administered intraperitoneally to Wistar rats was studied in both the plasma and the hippocampal microdialysate content.The samples were analyzed by reverse phased HPLC for the microdialysate samples and by HPLC with ion-exchange post-column derivatization (ninhydrin) for the plasma samples.In both plasma and microdialysate, we observed a dose dependent increase of taurine concentration. The AUC curves obtained from both microdialysate and plasma samples showed that the increase of taurine concentrations were linear. The mean ratio between AUC’s microdialysate and plasma was 1.63±0.21 showing thus an unbalance between plasma and brain taurine content; a mechanism which enhance taurine transfer from the plasma to the brain was assumed.

L-NNA Decreases Cortical Vascularization, Alcohol Preference and Withdrawal in Alcoholic Rats

Rats, which were made chronically alcoholic in combination with L-N(o)-nitro-arginine (L-NNA) treatment (5 mg/kg/day), a nitric oxide (NO) synthase inhibitor, showed a significant decrease in their alcohol preference and hypermotility during the withdrawal period by comparison with chronically alcoholic rats. However, no difference in the global liquid consumption between treated and untreated rats during the withdrawal stage was identified. In addition, the hypervascularization of the cortical area observed after chronic alcoholism was significantly decreased in the rats that had received L-NNA during the alcoholism procedure and was comparable to control rats. Thus, L-NNA alters both the behavioral preference for alcohol after alcoholism and the hypermotility during alcohol withdrawal, thus supporting the hypothesis of a direct implication of NO in alcohol abuse and its withdrawal.

Neurochemical pathways involved in the protective effects of nicotine and ethanol in preventing the development of Parkinson's disease: Potential targets for the development of new therapeutic agents.

In this short review, neurochemical targets are identified where nicotine, and possibly ethanol, may interact to prevent the occurrence of Parkinsons disease. These are (a) the nicotinic acetycholine receptors present in the nigrostriatal area or on the surface of microglia, (b) monoamine oxidases and (c) inducible nitric oxide synthase. If such induced changes can be verified in clinical studies, this may help in the design of new therapeutic drugs which may be of relevance to diminish the incidence and perhaps the progression of the debilitating condition of Parkinsons disease.

Nicotine-induced changes of glutamate and arginine in naive and chronically alcoholized rats: an in vivo microdialysis study.

The effects of nicotine, when administered either acutely or chronically, at doses of 0.15, 0.3 or 0.6 mg/kg, on the release of glutamate and arginine in the rat nucleus accumbens have been studied in microdialysis experiments. Glutamate release significantly increased after acute nicotine injection, 0.3 mg/kg, which was accentuated if there was a priming regime of saline for the previous 27 days. This is possibly related to the rewarding effects of nicotine. Five hours after cessation of chronic oral nicotine administration, there were significant increases in glutamate content, which was possibly reflective of a withdrawal process. Significant decreases in nucleus accumbens arginine release were evident, between 1 and 2 h, after chronic nicotine administration. When nicotine was co-administered to rats during chronic ethanol intoxication, at either 0.15 mg/kg or 0.3 mg/kg doses, glutamate release did not increase during the first 12 h of withdrawal. However, a decrease in arginine microdialysate content was still observed with all nicotine doses. The nicotine-induced changes in glutamate and arginine release in nucleus accumbens highlights the complex neuropharmacological interactions evoked by this compound and also identified its possible modulating effect on glutamate release during the initial stages of chronic ethanol withdrawal.

Taurine and ethanol preference: a microdialysis study using Sardinian alcohol-preferring and non-preferring rats.

Recent intracerebral microdialysis studies of different rat brain regions have shown that an acute ethanol injection induced a rapid dose-dependent increase in taurine microdialysate content during the first 60-min period. In taurine-supplemented rats, a reduced aversion for high ethanol doses was observed in a place conditioning paradigm, suggesting that taurine may be implicated in the regulation of some adverse effects of ethanol. The present study compares the effects of acute ethanol injections (1.0 and 2.0 g/kg, i.p.) on taurine nucleus accumbens microdialysate content in Sardinian ethanol-preferring (sP) and Sardinian ethanol-non-preferring (sNP) rats. While neither saline nor 1.0 g/kg ethanol injections had significant effect on taurine microdialysate concentration, 2.0 g/kg ethanol administration induced a rapid and significant increase in taurine microdialysate content in both sP and sNP rats. However, this ethanol-induced taurine release was significantly reduced in sP rats by comparison to sNP rats. As taurine is suggested to be released by brain cells to modulate different ethanol adverse effects, this lower taurine responsiveness to ethanol in sP rats by comparison to both sNP and Wistar rats may be a relevant indicator of reduced ethanol aversive effects in such animals and therefore be related to their higher alcohol consumption.

Anti-inflammatory actions of a taurine analogue, ethane β-sultam, in phagocytic cells, in vivo and in vitro.

The ability of a taurine prodrug, ethane β-sultam, to reduce cellular inflammation has been investigated, in vitro, in primary cultures of alveolar macrophages and an immortilised N9 microglial cell line and in vivo in an animal model of inflammation and control rats. Ethane β-sultam showed enhanced ability to reduce the inflammatory response in alveolar macrophages, as assayed by the lipopolysaccharide-stimulated-nitric oxide release, (LPS stimulated-NO), in comparison to taurine both in vitro (10 nM, 50 nM) and in vivo (0.15 mmol/kg/day by gavage). In addition, ethane β-sultam, (50, 100 and 1000 nM) significantly reduced LPS-stimulated glutamate release from N9 microglial cells to a greater extent than taurine. The anti-inflammatory response of taurine was shown to be mediated via stabilisation of IkBα. The use of a taurine prodrug as therapeutic agents, for the treatment of neurological conditions, such as Parkinsons and Alzheimers disease and alcoholic brain damage, where activated phagocytic cells contribute to the pathogenesis, may be of great potential.