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The effect of low concentrations of ethanol on Na+,K(+)-ATPase activity, defined as ouabain-inhibitable 86Rb+ (K+) uptake, was investigated in a crude synaptosome preparation which was subject to minimal subcellular fractionation procedures. Moderate (20-30%) but potent (EC50 = 3.8 mM) stimulation of total ouabain (1 mM)-inhibitable K+ uptake by ethanol was observed following incubation periods of up to 20 min. The activity of the ethanol-induced component of K+ uptake was antagonized by nanomolar concentrations of ouabain. Thus, the moderate stimulation of total ouabain-inhibitable K+ uptake by ethanol was attributable to the activation of a component of K+ uptake which was very sensitive (VS; IC50 = 2.8 x 10(-10) M) to inhibition by ouabain. Slightly higher concentrations of ouabain (10(-9) - 10(-6.6) M) stimulated K+ uptake above control (no ethanol or ouabain) in both the absence and presence of ethanol. The selectivity of the VS-ethanol interaction was demonstrated by the lack of any ethanol effect on two other components of ouabain-inhibitable K+ uptake which accounted for inhibition of K+ uptake by concentrations of ouabain above 10(-6.6) M and were defined as sensitive (S; IC50 = 10(-6) M) and insensitive (I; IC50 = 10(-4) M) to ouabain. These results define the ethanol-inducible component of ouabain-inhibitable Na+,K(+)-ATPase activity and promote the view that changes in Na+,K(+)-ATPase-dependent ion translocation may contribute to ethanol intoxication in vivo.

The inhalation toxicity of an ethanol-gasoline mixture was investigated in rats. Groups of 15 male and 15 female rats were exposed by inhalation to 6130 ppm ethanol, 500 ppm gasoline or a mixture of 85% ethanol and 15% gasoline (by volume, 6130 ppm ethanol and 500 ppm gasoline), 6 h a day, 5 days per week for 4 weeks. Control rats of both genders received HEPA/charcoal-filtered room air. Ten males and ten females from each group were killed after 4 weeks of treatment and the remaining rats were exposed to filtered room air for an additional 4 weeks to determine the reversibility of toxic injuries. Female rats treated with the mixture showed growth suppression, which was reversed after 4 weeks of recovery. Increased kidney weight and elevated liver microsomal ethoxyresorufin-O-deethylase (EROD) activity, urinary ascorbic acid, hippuric acid and blood lymphocytes were observed and most of the effects were associated with gasoline exposure. Combined exposure to ethanol and gasoline appeared to exert an additive effect on growth suppression. Inflammation of the upper respiratory tract was observed only in the ethanol-gasoline mixture groups, and exposure to either ethanol and gasoline had no effect on the organ, suggesting that an irritating effect was produced when the two liquids were mixed. Morphology in the adrenal gland was characterized by vacuolation of the cortical area. Although histological changes were generally mild in male and female rats and were reversed after 4 weeks, the changes tended to be more severe in male rats. Brain biogenic amine levels were altered in ethanol- and gasoline-treated groups; their levels varied with respect to gender and brain region. Although no general interactions were observed in the brain neurotransmitters, gasoline appeared to suppress dopamine concentrations in the nucleus accumbens region co-exposed to ethanol. It was concluded that treatment with ethanol and gasoline, at the levels studied, produced mild, reversible biochemical hematological and histological effects, with some indications of interactions when they were co-administered.

Background:The ventral tegmental area (VTA) is involved in regulating ethanol drinking, and the posterior VTA seems to be a neuroanatomical substrate that mediates the reinforcing effects of ethanol in ethanol‐naïve Wistar and ethanol‐naïve alcohol‐preferring (P) rats. The objective of this study was to test the hypothesis that chronic ethanol drinking increases the sensitivity of the posterior VTA to the reinforcing effects of ethanol.Methods:Two groups of female P rats (one given water as its sole source of fluid and the other given 24‐hr free‐choice access to 15% ethanol and water for at least 8 weeks) were stereotaxically implanted with guide cannulae aimed at the posterior VTA. One week after surgery, rats were placed in standard two‐lever (active and inactive) operant chambers and connected to the microinfusion system. Depression of the active lever produced the infusion of 100 nl of artificial cerebrospinal fluid (CSF) or ethanol. The ethanol‐naïve and chronic ethanol‐drinking groups were assigned to subgroups to receive artificial CSF or 25, 50, 75, or 125 mg/dl of ethanol (n= 6–9/dose/group) to self‐infuse (FR1 schedule) during the 4‐hr sessions given every other day.Results:Compared with the infusions of artificial CSF, the control group reliably (p < 0.05) self‐infused 75 and 125 mg/dl of ethanol but not the lower concentrations. The ethanol‐drinking group had significantly (p < 0.05) higher self‐infusions of 50, 75, and 125 mg/dl of ethanol than artificial CSF during the four acquisition sessions; the number of infusions of all three doses was higher in the ethanol‐drinking group than in the ethanol‐naive group. Both groups decreased responding on the active lever when artificial CSF was substituted for ethanol, and both groups demonstrated robust reinstatement of responding on the active lever when ethanol was restored.Conclusions:Chronic ethanol drinking by P rats increased the sensitivity of the posterior VTA to the reinforcing effects of ethanol.

1. The effect of 10 g 5,7-dihydroxytryptamine (5,7-DHT) micro-injected into both the dorsal (DRN) and the median raphe nuclei (MRN) on the intake of ethanol in the low alcohol drinking (LAD) rat was measured using a standard 3-30% ethanol preference test. 2. The combined lesion of both midbrain structures depleted the levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) significantly in each of eight major regions of the brain. The levels of norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) remained unchanged after the lesion. 3. The effects of the neurotoxin lesions on the intakes of ethanol, food, water and total amount of fluid consumed were not significant. 4. The results corroborate our previous findings with the Sprague-Dawley strain of rat and suggest that although brain 5-HT may play a role in the maintenance of basal patterns of ethanol drinking, this monoamine may not be able to modify further the consumption of this fluid after lesioning with 5,7-DHT.

Brain-to-blood transport, or efflux, systems play important roles in brain functions and can affect the CNS uptake and activity of endogenous and exogenous blood-borne substances. Several efflux systems have been described for peptides. These efflux systems may play important roles in communication between the CNS and peripheral tissues and may be important in conditions such as alcoholism.

Platelet aggregation, secretion of serotonin, and formation of thromboxane B2 induced by platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) were studied in plasma containing physiological concentrations of ionized calcium in eight alcoholics after cessation of heavy drinking. Responses of platelets of four nonalcoholic volunteers, matched with a subgroup of the alcoholics by age and sex, were also investigated. Aggregation of platelets from alcoholics was significantly less throughout the 6-day detoxification period compared with controls. Secretion of serotonin (5-hydroxy-tryptamine) was negligible and the production of thromboxane B2 was not detectable. Decreased platelet aggregability in response to aggregating agents, including platelet-activating factor, may be important in the development of hemorrhagic complications in alcoholics.

The effect of ethanol in vitro on inositol lipid metabolism in brain slices was investigated under nonstimulating and stimulating conditions. In cerebral cortical slices 100 microM norepinephrie (NE), 1 mM carbachol, 100 microM serotonin, 20 mM KCl, 1 mM glutamate and 30 microM A23187 stimulated inositide hydrolysis as measured by the release of [3H]inositol phosphates from [3H]myoinositol labeled slices. Ethanol (500 mM) inhibited nonstimulated inositide hydrolysis but had variable effects on stimulated inositide breakdown. NE-, KCl- and glutamate-stimulated [3H]inositol phosphate release was inhibited by 500 mM ethanol in the cortex. The inhibitory effect of ethanol on NE-stimulated inositide hydrolysis was concentration dependent and significant at concentrations as low as 100 mM. Inhibition by ethanol appeared to be noncompetitive. A similar pattern of inhibition by ethanol was observed when KCl was the stimulant. In hippocampal and hypothalamic slices, similar to cortical slices. NE- and KCl-stimulated inositide breakdown was significantly inhibited by ethanol. However, in brain stem slices, only KCl-stimulated [3H]inositol phosphate release was inhibited. Striatal slices stimulated by carbachol, NE and KCl were sensitive to the inhibitory effects of ethanol on inositol lipid breakdown. These results suggest that ethanol in vitro has specific effects on inositol lipid metabolism depending on the brain region studied and the type of stimulation. Moreover, the differential sensitivity to ethanol of stimulated inositide hydrolysis in the brain may contribute, at least in part, to some of the pharmacological effects of ethanol in vivo.

Background:  Ethanol (ETOH) consumption by pregnant women can result in Fetal Alcohol Spectrum Disorder (FASD). To date, the cellular targets and mechanisms responsible for FASD are not fully characterized. Our aim was to determine if ETOH can affect fetal human brain‐derived neural progenitor cells (NPC).Methods:  Neural progenitor cells were isolated by positive selection from normal second trimester fetal human brains (n = 4) and cultured, for up to 72 hours, in mitogenic media containing 0, 1, 10, or 100 mM ETOH. From 48 to 72 hours in culture, neurospheres generated in these conditions were filmed using time‐lapse video microscopy. At the end of 72 hours, neurosphere diameter and roundness were measured using videographic software. Mitotic phase analysis of cell‐cycle activity and apoptotic cell count were also performed at this time, by flow cytometry using propidium iodide (PI) staining. Real‐time PCR was used to estimate expression of genes associated with cell adhesion pathways.Results:  Neurosphere diameter correlated positively (r = 0.87) with increasing ETOH concentrations. There was no significant difference in cell‐cycle activity and no significant increase in apoptosis with increasing ETOH concentrations. Time‐lapse video microscopy showed that ETOH (100 mM) reduced the time for neurosphere coalescence. Real‐time PCR analysis showed that ETOH significantly altered the expression of genes involved in cell adhesion. There was an increase in the expression of α and β Laminins 1, β Integrins 3 and 5, Secreted phosphoprotein1 and Sarcoglycan ε. No change in the expression of β Actin was observed while the expression of β Integrin 2 was significantly suppressed.Conclusions:  ETOH had no effect on NPC apoptosis but, resulted in more rapid coalescence and increased volume of neurospheres. Additionally, the expression of genes associated with cell adhesion was significantly altered. ETOH induced changes in NPC surface adhesion interactions may underlie aspects of neurodevelopmental abnormalities in FASD.

Ethanol preference, a component of alcoholism, has been known for four decades to differ greatly between C57BL/6 and BALB/c inbred mouse strains. For mapping quantitative trait loci (QTLs) that affect ethanol preference, we used a set of B6.C Recombinant QTL Introgression (RQI) strains, which carry about 5% of the donor BALB/cJ (C) genome on a C57BL/6ByJ (B6) background. After characterizing males of the progenitor and RQI strains for variations in ethanol preference, we scanned their genome for polymorphisms at 244 dinucleotide-repeat marker loci known to differ between B6 and C. Because of the introgression of BALB/c-type QTLs onto the B6 background, some strains showed ethanol preference significantly lower or higher than that of the background strain, suggesting that genetic interaction between ethanol preference QTLs and the background can be operative. The genomic region showing the strongest influence on ethanol preference was on mouse chromosome 15, and corresponds to human chr.12q11-q13.