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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.

Acute oral administration of ethanol (3.2g/kg) to rats increased (DOPAC) levels in the caudate nucleus, but had no effect on DOPAC levels in the substantia nigra and frontal cortex and failed to modify dopamine content in any of the above areas. On the other hand, the administration of the same dose of ethanol to rats which had been chronically treated with ethanol (3.2g/kg daily for 60 days), produced a decrease of DA content and a parallel increase of DOPAC levels in all areas studied. In chronically treated rats, 24 hrs after last ethanol administration dopamine levels in the frontal cortex were 60% higher than in controls. The results suggest that ethanol administration causes dopamine release in different brain areas.

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.

AbstractNon‐adaptive activation of dopamine transmission in the nucleus accumbens shell by drugs of abuse has been attributed a fundamental role in the mechanism of drug addiction. In order to test this hypothesis, we compared in the same subject the effect of an addictive drug (ethanol) and of taste stimuli, including ethanol's own taste, on dialysate dopamine in the nucleus accumbens shell as an estimate of dopamine transmission and on taste reactivity as an expression of motivational valence. Ethanol was also monitored in the dialysates. In naive rats, intraoral infusion of a 20% sucrose + chocolate solution elicited a monophasic increase of dialysate dopamine immediately after the intraoral infusion. In contrast, intraoral infusion of 10% ethanol, 10% ethanol + 20% sucrose or 10% ethanol + 20% sucrose + chocolate solutions elicited a biphasic increase of nucleus accumbens dopamine with an early taste‐related rise and a late rise related to dialysate ethanol. Pre‐exposure to the ethanol solutions 24 h before resulted in the absence of the early dopamine rise and permanence of the late dopamine rise. This late dopamine rise was actually increased as compared with that of the nonpre‐exposed group when sucrose‐containing ethanol solutions were tested. The results indicate that single trial pre‐exposure to the ethanol solutions differentially affects the responsiveness of nucleus accumbens shell dopamine to the direct intracerebral action of ethanol and to the effect of its taste with potentiation, or no change of the first and abolition of the second. These observations point to the existence of major differences in the adaptive regulation of nucleus accumbens dopamine transmission in the shell after drug as compared with taste reward. These differences, in turn, are consistent with a role of nucleus accumbens shell dopamine in the mechanism of the behavioural effects of addictive drugs.

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.