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Previous studies on the adverse effects of perinatal exposure to ethanol (EtOH) on the developing visual system mainly focused on retinal and optic nerve morphology. The aim of the present study was to investigate whether earlier reported retinal and optic nerve changes are accompanied by anomalies in eye-specific fiber segregation in the dorsal lateral geniculate nucleus (dLGN). C57BL/6 mice pups were exposed to ethanol by intragastric intubation at either 3 or 4 g/kg from postnatal days (PD) 3-10, the third trimester equivalent to human gestation. Control (C) and intubation control (IC) groups not exposed to ethanol were included. On PD9, retinogeniculate projections were labeled by intraocular microinjections of cholera toxin-β (CTB) either conjugated to Alexa 488 (green) or 594 (red) administrated to the left and right eye, respectively. Pups were sacrificed 24 h after the last CTB injection. The results showed that ethanol exposure decreased the total number of dLGN neurons and significantly reduced the total dLGN projection as well as the contralateral and ipsilateral projection areas.

Human diamine oxidase (hDAO, EC 1.4.3.22) is the key enzyme in the degradation of extracellular histamine. Consumption of alcohol is a known trigger of mast cell degranulation in patients with mast cell activation syndrome. Ethanol may also interfere with enzymatic histamine degradation, but reports on the effects on DAO activity are controversial. There are also conflicting reports whether disulfiram, an FDA-approved agent in the treatment of alcohol dependence, inhibits DAO. We therefore investigated the inhibitory potential of ethanol and disulfiram and their metabolites on recombinant human DAO (rhDAO) in three different assay systems. Relevant concentrations of ethanol, acetaldehyde, and acetate did not inhibit rhDAO activity in an in vitro assay system using horseradish peroxidase (HRP) -mediated luminol oxidation. The aldehyde dehydrogenase (ALDH; EC 1.2.1.3) inhibitors cyanamide and its dimer dicyanamide also had no effect on DAO activity. In one assay system, the irreversible ALDH inhibitor disulfiram and its main metabolite diethyldithiocarbamate seemed to inhibit DAO activity. However, the decreased product formation was not due to a direct block of DAO activity but resulted from inhibition of peroxidase employed in the coupled system. Our in vitro data do not support a direct blocking effect of ethanol, disulfiram, and their metabolites on DAO activity in vivo.

The initiation phase of ethanol self-administration is difficult to study using the well-established, sucrose-fading procedure due to the changing concentrations of ethanol in the first few days. The purpose of this experiment was to test whether a modified sucrose-substitution procedure in which rats are initially exposed to high concentrations of ethanol and sucrose for three days would successfully initiate ethanol self-administration. Male Long-Evans rats were trained to lever-press with a 10% sucrose solution in which four or 20 responses allowed 20-min access to the solution. Subsequently, rats were exposed to a 3-day period of operant self-administration of 10% sucrose+10% ethanol. This constant-concentration exposure was followed by the standard procedure in which sucrose is completely faded out. The establishment of ethanol self-administration was determined by ethanol intake, pre- and postprocedure two-bottle choice preference tests, and extinction trials. The mean ethanol intake was 2.2 times higher on day 2 compared with day 1 on the 10% sucrose+10% ethanol solution. After fading out the sucrose, the daily intake of 10% ethanol solution over 5 days was stable at approximately 0.57 g/kg. Ethanol preference was approximately threefold higher after the modified sucrose-fading procedure. Responding during a single session extinction test was dramatically increased from 4 to 61+/-13 or 20 to 112+/-22 responses in 20 min. Similar to the standard sucrose-fading method, we did not observe a significant relationship between extinction responding and ethanol intake. Blood alcohol concentrations were 4.5 mM 20 min after consumption began. We conclude that initiation and establishment of ethanol self-administration will occur using this modified sucrose-fading procedure.

This study was designed to test the hypothesis that chronic prenatal ethanol exposure decreases basal and stimulated L-glutamate release in the hippocampus of young, postnatal guinea pigs. Timed, pregnant guinea pigs were randomly assigned to one of the following three chronic treatment groups: 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose and pair-feeding to the ethanol group, and water. Each oral treatment was given daily throughout gestation. Spontaneous locomotor activity was increased on postnatal day (PD) 10, and brain and hippocampal weights were decreased on PD 12 in the offspring of the ethanol group compared with the isocaloric-sucrose/pair-fed and water groups. On PD 12, the 45 mM K(+)- and 10 microM veratridine-stimulated release of glutamate in transverse hippocampal slices was decreased in the ethanol group compared with the two control groups. This alteration in glutamate release produced by chronic prenatal ethanol exposure may decrease the efficiency of excitatory synaptic transmission in the hippocampus during postnatal life.

Carbamazepine (CBZ) has been used in the treatment of alcohol withdrawal (AW). However, cases of induction of euphoric feelings when mixed with alcohol have been reported. We verified whether CBZ could potentiate ethanol stimulatory effects in animals. Two groups of mice were injected with saline (group I) or 2 g/kg ethanol (group II) IP, for 20 days. On the next day, each group was divided into two subgroups that received either a single dose of CBZ (10 mg/kg) or vehicle IP, followed, 30 min later, by saline or ethanol injection. Locomotor activity was measured. Acute CBZ did not change locomotor activity of ethanol-treated mice. Treatment with CBZ or vehicle continued for 6 days. Finally, on the 28th day, 30 min after the last CBZ or vehicle injection, an ethanol challenge was given to group II and a saline injection to group I. The results showed a significant potentiation of ethanol stimulatory effects by chronic CBZ treatment. Data indicated that CBZ should be cautiously administered to alcohol-dependent patients.

Alcohol consumption leads to an exaggerated inflammatory response after burn injury. Elevated levels of interleukin-6 (IL-6) in patients are associated with increased morbidity and mortality after injury, and high systemic and pulmonary levels of IL-6 have been observed after the combined insult of ethanol exposure and burn injury. To further investigate the role of IL-6 in the pulmonary inflammatory response, we examined leukocyte infiltration and cytokine and chemokine production in the lungs of wild-type and IL-6 knockout mice given vehicle or ethanol (1.11 g/kg) and subjected to a sham or 15% total body surface area burn injury. Levels of neutrophil infiltration and neutrophil chemoattractants were increased to a similar extent in wild-type and IL-6 knockout mice 24 h after burn injury. When ethanol exposure preceded the burn injury, however, a further increase of these inflammatory markers was seen only in the wild-type mice. Additionally, signal transducer and activator of transcription-3 (STAT3) phosphorylation did not increase in response to ethanol exposure in the IL-6 knockout mice, in contrast to their wild-type counterparts. Visual and imaging analysis of alveolar wall thickness supported these findings and similar results were obtained by blocking IL-6 with antibody. Taken together, our data suggest a causal relationship between IL-6 and the excessive pulmonary inflammation observed after the combined insult of ethanol and burn injury.

Angiotensin (Ang) II-stimulated phosphorylation of signal transducer and activator transcription (STAT) 3 in rat hepatocytes and the effects of ethanol on this activation were investigated. Angiotensin II (100 nM) stimulated Tyr705 and Ser727 phosphorylation of STAT3 and formation of sis-inducing factor complexes. In the presence of U-0126 (10microM), a p42/44 mitogen-activated protein kinase (MAPK) kinase inhibitor, Ang II further increased Tyr705 phosphorylation of STAT3 but completely abrogated Ser727 phosphorylation of STAT3. Inhibition of p42/44MAPK also increased STAT3 DNA-binding activity. Pretreatment with ethanol (100mM) for 24h resulted in decrease in Tyr705 phosphorylation of STAT3 by ethanol alone and inhibition of Tyr705 phosphorylation of STAT3 stimulated by Ang II. Although ethanol potentiates Ang II stimulated p42/44 MAPK activation in hepatocytes, ethanol inhibited Ser727 phosphorylation of STAT3 stimulated by Ang II. Angiotensin II-stimulated STAT3-binding activity was not significantly affected by ethanol treatment. These results suggest a negative regulation of Ang II-stimulated STAT3 tyrosine phosphorylation and STAT3-binding activity through p42/44 MAPK activation in hepatocytes. However, ethanol modulation of Ang II-stimulated STAT3 phosphorylation occurs by MAPK independent mechanisms. Ethanol potentiation of MAPK signaling without suppression of STAT3 function may modulate the course of alcoholic liver injury.

The brain undergoes substantial maturation during adolescence, and repeated exposure to ethanol at this time has been shown to result in long-lasting behavioral and neural consequences. During the broad period of adolescence, different neuronal populations and circuits are refined between early and late adolescence, suggesting the possibility that ethanol exposure at these differing times may lead to differential outcomes. The goal of the current study was to evaluate the impact of adolescent intermittent ethanol (AIE) during early and late adolescence on the formation of goal-directed and habitual behavior in adulthood. Male and female Sprague-Dawley rats were exposed to ethanol via intragastric gavage (4.0 g/kg, 25% v/v) every other day from postnatal day (P) 25-45 or P45-65, considered early and late adolescence, respectively. In adulthood (~P70 early or ~ P90 late), rats were gradually food-restricted and began operant training on a fixed ratio 1 schedule. Rats were then transitioned onto random interval schedules and eventually underwent a sensory-specific satiation procedure as a model of reward devaluation. Few differences as a result of adolescent ethanol exposure were found during instrumental training. Following reward devaluation, rats exposed to water and ethanol during early adolescence exhibited reductions in lever pressing, suggestive of a goal-directed response pattern. In contrast, late AIE males and females demonstrated persistent responding following both devalued and non-devalued trials, findings representative of a habitual behavior pattern. The shifts from goal-directed to habitual behavior noted only following late AIE contribute to the growing literature identifying specific behavioral consequences as a result of ethanol exposure during distinct developmental periods within adolescence. More work is needed to determine whether the greater habit formation following late AIE is also associated with elevated habitual ethanol consumption.