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Summary: The potential role of genetic factors in the etiology of posttraumatic and alcohol‐associated seizures was studied in 289 male patients with recurrent seizures and in 174 individuals who had never experienced a seizure. The incidence of seizures in first‐degree relatives of probands was compared with that in relatives of unaffected individuals. Relatives of patients with alcoholassociated seizures had a rate ratio of 2.45 [95% confidence interval (CI) 1.41–4.251, whereas no excess incidence was noted among relatives of posttraumatic epilepsy patients (rate ratio 1.20, 0.64–2.25 CI). Relatives of probands with both antecedents showed an intermediate rate ratio of 1.72 (0.92–3.20 CI). Among probands with alcohol‐associated seizures, the rate ratio of 2.05 for patients with alcohol‐related seizures (i.e., spontaneously occurring seizures in association with chronic alcohol abuse) was slightly higher than that of 1.85 for probands with alcohol withdrawal seizures. Trauma severity had a slight impact on the incidence of affected relatives; patients with severe head injuries had a rate ratio of 0.73 and probands with milder trauma had a rate ratio of 0.99. The results indicate a limited, if any, role of genetic predisposition in development of posttraumatic seizures. Alcoholrelated seizures, however, showed familial aggregation of unprovoked seizures, suggesting an involvement of genetic factors in the origin of such seizures.

Alcoholism and alcohol abuse create costly social and economic problems in many nations. Recent studies indicate that alcohol exposure during adolescence may convey unique risks for subsequent neurocognitive deficits and problem drinking. Although GABA(A) receptor function is one of the principle neurochemical targets of ethanol action in the adult brain, little is known about the effects of alcohol on this system during adolescence. Adolescent (30-day-old) and adult (90-day-old) male rats were intermittently exposed to ethanol for 1 month. At various times after the end of the exposure period, synaptoneurosomes were prepared from their cerebral cortices. GABA(A) receptor-mediated 36Cl(-) influx was measured in the absence and presence of the neurosteroid 3alpha,21-dihydroxy-5alpha-pregnan-20-one (THDOC). In tissue from ethanol-exposed animals, sensitization to the potentiating effects of the neurosteroid was apparent 5 and 12 days after ethanol withdrawal. This sensitization was more apparent at the low concentrations of THDOC in animals pretreated with ethanol as adolescents. Sensitization to the potentiating effects of a neurosteroid is an enduring phenomenon, persistent long after the acute phase of ethanol withdrawal, and may be indicative of long-term changes in GABA(A) receptor function. Enhanced neurosteroid sensitization in animals pretreated as adolescents is consistent with the notion that adolescence is a period of unique sensitivity to the effects of ethanol. This uniqueness may now be extended to the chronic effects of ethanol.

In CA1-CA3 hippocampal slices, in vitro ethanol (EtOH) (10-100 mM) evoked, as a function of EtOH concentration, a differential release of aspartate (Asp) and glutamate (Glu). Omission of Ca2+ ions from the superfusion media completely abolished the EtOH-induced release of Asp but not that of Glu. In addition, at 20 mM, EtOH enhanced K(+)-evoked release only of Asp. Finally, delayed changes were observed on NMDA-evoked release of [3H]noradrenaline (NA) in the dentate gyrus (DG) after withdrawal from EtOH for 30 days.

Male mice of the BALB/c strain were given a solution of 15% ethanol as their only source of fluid for periods varying from 5 weeks to 8 months. For behavioral testing, they were compared with control groups which had received either an isocaloric solution of sucrose or tap water. Memory was tested by using spontaneous alternation behavior in a T maze. Each test consisted of two forced trials (acquisition) followed by a free trial (test) given at different acquisition--test intervals (from 30 s to 24 h). Results from two independent experiments showed that after 25 weeks of ethanol administration there was an accelerated rate of decay of spontaneous alternation as a function of the acquisition--test interval. Such a phenomenon persisted after ethanol was omitted from the diet. A third experiment showed that when tested on two successive sessions separated by a 5 h interval, experimental subjects exhibited a decreased ability to perform normally on the second test. Our data are interpreted as showing that long-term ethanol administration results in accelerated forgetting and increased vulnerability to proactive interference and, as such, they are compared to the memory dysfunctions observed in amnesic patients.

Previous studies from our laboratory revealed that acute ethanol exposure inhibits phosphorylation of mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinases (ERK) in mice. In the present study, we have further investigated effect of chronic administration of ethanol on tyrosine kinase phosphorylation of GABA(A) receptor subunits in the mouse cultured cortical neurons. We observed that there was an up-regulation in tyrosine kinase phosphorylation of the GABA(A) receptor beta(2) and gamma(2) subunits following chronic ethanol exposure, whereas there was no effect on alpha(1) subunit of the GABA(A) receptor in the cultured cortical neurons of mice as determined by Western blotting. These results suggest a potential role for tyrosine kinase phosphorylation of some of the GABA(A) receptor subunits in chronic ethanol-induced tolerance and dependence.

The drug discrimination paradigm was used to evaluate the behavioral differences in response to ethanol between three strains of rats, viz., Sprague-Dawley, N/Nih and Fawn-Hooded. This latter group is thought to have a genetically-transmitted diminished central serotonin function. Each group of rats was trained to discriminate between the stimulus properties of 600 mg/kg ethanol and its vehicle in a two-lever, food-motivated operant task. Results indicate that the Fawn-Hooded rats required a significantly longer time and a higher ethanol dose to reach criterion discrimination performance. Furthermore, the ED50 value of the Fawn-Hooded rats, once trained, was higher than the Sprague-Dawley or N/Nih rats. The possibility that a reciprocal relationship exists between lowered central serotonin concentrations and higher alcohol consumption is suggested and the hypothesis that the diminished ability to recognize the interoceptive stimuli produced by ethanol may result in larger amounts of ethanol being consumed is offered.

Using two inbred strains of mice which have similar rates of alcohol metabolism, we asked whether prenatal alcohol exposure would cause greater incidence and severity of defects in the development of two forebrain fiber tracts, the corpus callosum and the anterior commissure, in mice prone to these defects (BALB/c) than in mice not prone to these defects (C57BL/6). Pregnant animals were fed 0.6 kcal/g body weight of a Sustacal-based liquid diet containing 0, 15, 17.5, 20, or 25% ethanol-derived calories from day 7 to fetal assessment on day 18 of gestation. Most of alcohol's greatest effects and the greatest strain differences in alcohol's effects on fetal variables were produced by the 17.5% diet. This dose had inhibitory effects on fetal body, brain, and midsagittal corpus callosum and anterior commissure growth. All these effects, except that on brain weight, were significantly greater in C57s than in BALBs. When the results were compared with prenatal growth curves for normal untreated mice, the effect of alcohol on corpus callosum but not anterior commissure growth was largely explained by its effects on overall development. The 17.5% diet had a greater specific effect on size of the anterior commissure in C57s than BALBs but increased the incidence and severity of its permanent dysmorphology in BALBs more than in C57s. Anterior commissure size and morphology may be sensitive indicators of alcohol's effects on prenatal brain development. Hereditary differences in rate of maternal alcohol metabolism no doubt have important consequences for risks arising from prenatal alcohol exposure. However, this study clearly indicates that inherited factors, other than those that influence rate of alcohol metabolism, are important influences on the overall fetal response and the specific responses of the anterior commissure to prenatal alcohol exposure.

Effects of nicotine, administered by continuous infusion via osmotic minipumps, were studied on the operant self-administration of alcohol by rats, using a variable interval (15 s) schedule, and measuring the acquisition, maintenance, extinction and reinstatement of responding for alcohol. Doses of nicotine of 0.25, 1.25 and 7.5 mg/kg/24 h had no significant effects on the maintenance of responding for alcohol, but 5 mg/kg/24 h nicotine resulted in a significant increase in responding on the lever delivering the reward when water was substituted for the alcohol, indicating delayed extinction of responding. During infusion of 2.5 mg/kg/24 h nicotine, responding was significantly greater over the "sucrose-fading" training sessions, during acquisition of responding, when mixtures of alcohol and sucrose were provided as reward. When minipumps infusing 2.5 mg/kg/24 h nicotine were implanted after the alcohol responding had been acquired, the responding for alcohol increase during the first week of nicotine infusion, but corresponding nicotine infusion doses of 0.25, 1.25 and 7.5 had no significant effects. The results indicate that nicotine can increase operant responding for alcohol and this is crucially dependent on the dose of nicotine and the time of testing. The results have implications for the frequently encountered dependence on the combination of alcohol and nicotine.