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Placebo alcohol administered via a new device induced intoxication in 7 of 10 healthy adult males. Intoxication levels reported after placebo alcohol was 36% of intoxication ratings after real alcohol when peak blood alcohol values reached 84 mg/dl. Since expectancy about alcohol effects may contribute significantly to perceived intoxication, the new device should facilitate alcohol administration studies which would benefit from a placebo control.

Chronic alcohol abuse depresses the nervous system and, upon cessation, rebound hyperexcitability can result in withdrawal seizure. Withdrawal symptoms, including seizures, may drive individuals to relapse, thus representing a significant barrier to recovery. Our lab previously identified an upregulation of the thalamic T-type calcium (T channel) isoform CaV3.2 as a potential contributor to the generation and propagation of seizures in a model of withdrawal. In the present study, we examined whether ethosuximide (ETX), a T-channel antagonist, could decrease the severity of ethanol withdrawal seizures by evaluating electrographical and behavioral correlates of seizure activity. DBA/2J mice were exposed to an intermittent ethanol exposure paradigm. Mice were treated with saline or ETX in each withdrawal period, and cortical EEG activity was recorded to determine seizure severity. We observed a progression in seizure activity with each successive withdrawal period. Treatment with ETX reduced ethanol withdrawal-induced spike and wave discharges (SWDs), in terms of absolute number, duration of events, and contribution to EEG power in the 6-10 Hz frequency range. We also evaluated the effects of ETX on handling-induced convulsions. Overall, we observed a decrease in handling-induced convulsion severity in mice treated with ETX. Our findings suggest that ETX may be a useful pharmacological agent for studies of alcohol withdrawal and treatment of resulting seizures.

This study was performed to determine the long-term effects of ethanol exposure during the brain growth spurt (postnatal days 4-10) on the number of parvalbumin-immunoreactive (PA+) GABAergic neurons in the adult (P60) rat medial septum and anterior cingulate cortex. Significant loss of neurons within each of these populations has previously been demonstrated following prenatal ethanol exposure. In the present study, no significant differences in the number of PA+ neurons were found in either the medial septum or the cingulate cortex when control and ethanol-exposed animals were compared. The cellular densities and volumetric measures in both brain regions were also similar in the two groups. We speculate that compensatory up-regulative mechanisms may have accounted for the protection of the PA neuronal populations in these two areas following the early neonatal exposure.

In the past 15 years, both human and animal studies have advanced our understanding of the effects of adolescent alcohol exposure on behavioral and neural development, particularly in the areas of the ontogeny of initial sensitivity and tolerance to alcohol, the consequences of adolescent alcohol exposure on subsequent drinking patterns, as well as cognitive and neural function. Despite these advances, there are still substantial gaps in our understanding of whether heavy adolescent drinking interferes with normal brain development at the cellular and molecular level, and if so, how these changes may translate into patterns of brain connectivity that result in the emergence of alcohol use disorders. This article discusses our current knowledge of the cellular and molecular brain changes that stem from heavy alcohol exposure, including binge patterns, during adolescence. Progress has been made in linking the behavioral effects of adolescent drinking to underlying cellular and molecular mechanisms. However, it is suggested that future research on the etiology and consequences of adolescent drinking use an integrative approach to this problem by combining multiple levels, including genetic, cellular and molecular, systems (neuroimaging), and behavioral, with an emphasis on integrating the different levels of analysis.

Acute administration of ethanol reportedly decreases total sialic acid in brain. Here, we tested the hypothesis in brain and liver that the decrement is due to increased hydrolysis of sialoglycoconjugates. Mouse tissue slices were pulse-labeled with N-[3H]acetyl-D-mannosamine, the precursor of sialic acid. Incorporation was linear for up to 4 hr of incubation. When the labeled slices were incubated with three concentrations of ethanol (0.1, 0.5, and 1 M) for 5 hr, labeled liver sialoconjugates were significantly affected only at 0.5 and 1 M ethanol, whereas labeled brain sialoconjugates were markedly decreased even at 100 mM ethanol. Sialidase activity decreased steadily with increasing concentration of ethanol, indicating that the increased hydrolysis was not attributable to an enhanced sialidase activity. n-Propanol and t-butanol had the same degradative effect as ethanol on sialocompounds; and 3 mM pyrazole, an inhibitor of alcohol dehydrogenase (ADH), had no effect on ethanol-induced degradation of sialocompounds. The protein/DNA ratio in liver showed a steady decrease with increasing ethanol. The data thus confirm the in vivo reports of ethanol-enhanced cleavage and rule out any increase in sialidase activity as a major cause.

Endocrine feedback of testosterone (T) in regulation of the hypothalamus is via the effects of T on the noradrenergic system. The current experiment was performed to determine the effects of fetal ethanol exposure (FEE) on the norepinephrine (NE) and dopamine (DA) content in the hypothalamic-preoptic area (HPOA) of adult male rats, and the response of NE and DA to T administration. Pregnant rats were exposed to diets containing either a liquid diet containing ethanol, a liquid diet containing sucrose isocalorically substituted for ethanol, or a chow and water diet. Male offspring were castrated or sham-operated at 45 days of age. The animals received either testosterone propionate (TP) or an oil vehicle. HPOA was collected at 55 days of age from each animal and NE and DA content was measured by HPLC-EC. There was no significant alteration of NE or DA content in the HPOA in FEE animals compared to catecholamine levels in animals derived from dams on the control diets. Castration had no significant effect on NE and DA content in the chow-fed or pair-fed animals. TP administration significantly reduced NE content only in the chow- and pair-fed animals but not in the FEE animals. DA content in the HPOA was not affected by castration, but TP administration also resulted in significantly reducing DA content in chow- and pair-fed castrate male rats but not in FEE castrate male rats. The results indicate that FEE alters the response of the noradrenergic and dopaminergic neurons in the HPOA to T administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The alcohol-sensitive ANT and the alcohol-insensitive AT rat lines developed by selective breeding for differential sensitivity to motor impairment on the tilting plane by a moderate ethanol dose (2 g/kg, IP), were cross-bred to produce second generation (F2) offspring to study phenotypic correlations between various behavioral and biochemical properties and the degree of initial alcohol sensitivity in the tilting plane test. The F2 population (n = 75) was subjected to alcohol sensitivity tests using a tilting plane test and a sleep time test, and to the elevated plus-maze test of sober activity and anxiety. Finally, the animals were sacrificed and the concentrations of dopamine and its acidic metabolites were analyzed in their striatal tissues. Serum corticosterone was determined to obtain information about the stress responses of the animals after the tilting plane test. The behaviors studied had no significant correlations with each other, suggesting that the various genetic and environmental factors affecting these behavioral phenotypes are different for each behavior. The biochemical measures yielded some correlations with the tilting plane test results that were contrary to the differences between the parent rat lines (dopaminergic indices) or that were confounded by the correlations with the body weight of the animals (corticosterone). Body-weight independent correlational tendency between the alcohol-induced impairment in motor performance and serum corticosterone concentration, however, fitted the differences between the parent lines, suggesting that stress mechanisms cannot be fully excluded as factors contributing to the differential alcohol sensitivity between the ANT and AT rat lines.

The influence of varying the ratios of [Na+]/[K+] on the effects of alcohol (500 mg/dl) on brain (Na+ + K+)-ATPase, using a commercial porcine enzyme preparation, showed that, generally, activity was stimulated by ethanol when [Na+] less than [K+], but inhibited when [Na+] greater than [K+] (with sum kept constant at 150 mM). In addition, when [Na+]/[K+] was 15/90 mM, representative of normal intracellular levels, ethanol (500 mg/dl) stimulated the porcine enzyme, but inhibited it when [Na+]/[K+] was 144/6 mM, representative of normal extracellular levels. Similarly, in freshly prepared enzyme from highly purified rat brain synaptic membranes, ethanol (100, 300, and 450 mg/dl) stimulated when [Na+]/[K+] was 15/88 mM (representing intracellular levels), but inhibited when [Na+]/[K+] was 142/4 mM (extracellular levels).

The activity of norepinephrine (NE) within the thermosensitive region of the anterior hypothalamic, pre-optic area (AH/POA) of the rat was examined in relation to changes in core temperature produced by ethyl alcohol. Following stereotaxic implantation of push-pull guide tubes, a specific site in the AH/POA, reactive or non-reactive to NE, was labeled with 1.0 microliter of [3H]-NE. Alcohol in a concentration of 2.75% or 5.5% was then perfused locally at the same site by push-pull cannulae or administered peripherally in a dose of 2.0 g/kg. In control experiments, artificial CSF was perfused alone. The perfusion of alcohol enhanced or delayed the release of [3H]-NE in AH/POA or failed to alter the efflux of the catecholamine, with the specific response dependent principally on the: (1) anatomical site of hypothalamic perfusion, (2) concentration of alcohol, and (3) interval of perfusion itself. During the perfusion of alcohol within a very circumscribed region in the AH/POA, vasodilatation, as reflected by an increase in skin temperature, and a hypothermia of short latency, occurred. The change in core temperature was usually accompanied by a delay in the efflux of [3H]-NE. After the peripheral administration of 2.0 g/kg alcohol, an alteration in NE efflux from the AH/POA was also induced during the course of a hypothermic response accompanied by vasodilatation. These results suggest that alcohol exerts a direct central effect on nerve cells comprising the thermoregulatory mechanism located within the hypothalamus. Further, the well-known thermolytic effect of alcohol could be mediated in part by noradrenergic synapses within AH/POA, by means of their phasic release of NE.