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When rats are presented with a novel saccharin solution and immediately injected with either morphine or ethanol, they subsequently develop a conditioned taste aversion (CTA) to the saccharin solution which reflects the aversive component of the conditioning drug. The present study provides evidence which suggests that both morphine-induced and ethanol-induced CTAs can be blocked by the specific high-affinity binding opiate antagonist, naloxazone.

Young and aged rats were treated chronically with ethanol or scopolamine. Muscarinic receptors were measured in cerebral cortex, hippocampus and striatum. Following scopolamine treatment muscarinic receptor density in cerebral cortex, hippocampus and striatum of young rats increased by 34, 57 and 27%, respectively; in brains of aged rats the increase was 41% in cerebral cortex, 43% in hippocampus and nil in striatum. Affinity of muscarinic receptors was not changed by scopolamine treatment. Following chronic ethanol administration there was a 48% increase in cortical muscarinic receptor density in young, but not aged rats. The density of muscarinic receptors in hippocampus and striatum of both young and aged rats was not affected by ethanol treatment. Affinity of receptors in hippocampus of aged, ethanol-treated rats was increased compared to age-matched controls. Adaptative responses of the muscarinic receptor/transducer system to neurotransmitter availability are present in both young and aged rats, both the ethanol-induced response is present only in young animals. This suggests differences in the mechanism of action of ethanol and receptor agonists and antagonists in modulating receptor plasticity.

Previous studies have demonstrated that there is a bidirectional modulation of ethanol-induced locomotion produced by drugs that regulate brain catalase activity. In the present study we have assessed the effect in rats of intraperitoneal, intraventricular or intracraneal administration of the catalase inhibitor sodium azide in the locomotor changes observed after ethanol (1 g/kg) administration. Our results show that sodium azide prevents the effects of ethanol in rats locomotion not only when sodium azide was systemically administered but also when it was intraventricularly injected, then confirming that the interaction between catalase and ethanol takes place in Central Nervous System (CNS). Even more interestingly, the same results were observed when sodium azide administration was restricted to the hypothalamic Arcuate nucleus (ARC), a brain region which has one of the highest levels of expression of catalase. Therefore, the results of the present study not only confirm a role for brain catalase in the mediation of ethanol-induced locomotor changes in rodents but also point to the ARC as a major neuroanatomical location for this interaction. These results are in agreement with our reports showing that ethanol-induced locomotor changes are clearly dependent of the ARC integrity and, especially of the POMc-synthesising neurons of this nucleus. According to these data we propose a model in which ethanol oxidation via catalase could produce acetaldehyde into the ARC and to promote a release of beta-endorphins that would activate opioid receptors to produce locomotion and other ethanol-induced neurobehavioural changes.

Previous studies suggest that the nucleus accumbens shell (AcbSh) and core (AcbC) regions may have distinct roles in ethanol consumption. N-Methyl-d-aspartate receptor 1 (NMDAR1), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinases (ERKs) have been demonstrated to contribute to and possibly interact in the molecular mechanism underlying ethanol dependence and relapse. However, little is known regarding the mechanisms underlying the effects of ethanol exposure, withdrawal, and re-exposure, particularly with regard to NMDAR1-CaMKII-ERK signaling in accumbens subregions. In the present study, rats were provided with a 6% ethanol solution as their only drinking source. We found that ethanol exerted locomotor stimulant and anxiolytic effects in open field behaviors. Phosphorylation of NMDAR1, CaMKII and ERK was significantly decreased in the AcbSh and AcbC following chronic ethanol exposure. Ethanol withdrawal increased phospho-NMDAR1 and phospho-CaMKII expression in the AcbSh. Ethanol withdrawal also induced an increase of phospho-ERK1/2 in both the AcbSh and AcbC, while ethanol re-exposure decreased phospho-ERK in the AcbSh. These results indicated that the activation of NMDAR1-CaMKII-ERK signaling in the AcbSh but not the AcbC would contribute more to ethanol drinking and chronic ethanol-related negative emotional states.

Using the unbiased disector method we have shown that chronic alcohol consumption induces a significant decrease of dentate gyrus granule cell density in alcohol-fed rats for 18 months. A still more dramatic reduction was observed in a group of age-matched rats alcohol-fed for 12 months and switched to water for 6 months (recovery group). These results indicate that a progressive neuronal loss of the hippocampal granule cells in not impeded after cessation of alcohol intake. It is thus suggested that once the mechanisms underlying the alcohol-induced neuronal degeneration are triggered, they continue to act even after withdrawal.

The presence of a sexually receptive female behind perforated transparent partition induced sexual arousal and specific behavior in male mice so they spent more time near partition in an attempt to make their way to the female. Three-chambered free-choice model was used to evaluate sexual partner preference. The main pattern of sexual preference was the time spent by a male mouse at the partition dividing female (F-partition time) versus a partition dividing male (M-partition time). Pregnant mice were given ethanol (11vol.%) for 1-21 gestational days, and were exposed to restraint stress (2h daily for 15-21 day of the gestation). Control pregnant mice had free access to water and food and were not stressed. Adult male offspring of ethanol and stress exposed dams (E+S) showed decreased F-partition time and increased M-partition time. Whereas F-partition time in all control mice prevailed over M-partition time, 78% E+S mice demonstrated prevailed M-partition time. E+S mice were more active in social interaction with juvenile male. No significant differences between E+S and control mice in the open field and novelty tests were revealed. Therefore, E+S exposure during dam gestation inverted sexual partner preference in male offspring, suggesting that stress and alcohol in pregnancy produces predisposition to homosexuality.

We studied the in vitro effects of ethanol (25, 50 and 100 mM) on pyroglutamyl aminopeptidase activity (pGluAP), which has been reported as thyrotrophin-releasing-hormone-degrading activity. pGluAP was measured in presence or absence of calcium, under basal and K(+)-stimulated conditions, in synaptosomes and their incubation supernatant, using pyroglutamyl-beta-naphthylamide as substrate. In basal conditions, in synaptosomes, pGluAP was inhibited by ethanol in a calcium-independent way. In the supernatant, the response differed depending on the concentration of ethanol. Depolarization with K(+) modified pGluAP in synaptosomes and supernatant depending on the presence or not of calcium. In synaptosomes, in absence of calcium, the activity was inhibited at the highest concentrations of ethanol. In contrast, in the supernatant, under depolarizing conditions, ethanol increases pGluAP in absence of calcium. These changes may be in part responsible of the behavioural changes associated to alcohol intake.

The exact mechanism of brain atrophy in patients with chronic alcoholism remains unknown. There is growing evidence that chronic alcoholism is associated with oxidative stress and with a derangement in sulphur amino acid metabolism (e.g. ethanol-induced hyperhomocysteinemia). Furthermore, it has been reported that homocysteine induces neuronal cell death by stimulating N-methyl-D-aspartate receptors as well as by producing free radicals. To further evaluate this latter hypothesis we analysed serum levels of both homocysteine and markers of oxidative stress (malondialdehyde) in alcoholic patients who underwent withdrawal from alcohol. Homocysteine and malondialdehyde were quantified by high performance liquid chromatography (HPLC) in serum samples of 35 patients (active drinkers). There was a significant correlation (P<0. 01) between blood alcohol concentration and elevated homocysteine (Spearman's r=0.71) and malondialdehyde (r=0.90) levels on admission. In addition, homocysteine and malondialdehyde levels were found to be significant decreased after 3 days of withdrawal treatment (Wilcoxon test: homocysteine, Z=-5.127; malondialdehyde, Z=-3.120; P<0.01). We postulate that excitatory neurotransmitters and mechanisms of oxidative stress in patients with chronic alcoholism may partly mediate excitotoxic neuronal damage and hereby cause brain shrinkage.