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AbstractThis study involved mice that received 4 days of ethanol (EtOH) vapor inhalation and then were assessed for type 1 inositol 1,4,5‐trisphosphate receptor (IP3Rs‐1) expression and the development of EtOH‐induced place preference at various time points in withdrawal. IP3R‐1 protein was found to be significantly increased in the nucleus accumbens (NAcc) of mice immediately after 4‐day EtOH vapor inhalation, while it significantly reduced to the control level during the next 3 days of withdrawal from EtOH inhalation. EtOH (2 g/kg, i.p.)‐induced place preference after 3 days of withdrawal from EtOH vapor inhalation increased dose dependently for 4 days, which was significantly inhibited by 2‐aminophenoxyethane‐borate, an antagonist for IP3Rs. EtOH conditioning significantly increased, compared to alcohol‐naïve control mice, both IP3R‐1 protein and the release of dopamine in the NAcc of mice after 3 days of withdrawal from EtOH vapor inhaled for 4 days, and this increase of IP3R‐1 protein was completely abolished by intracerebroventricular injection of FK506, an inhibitor for calcineurin. These results indicate that the sensitization of EtOH‐induced place preference is due to up‐regulated IP3R‐1 via calcineurin‐mediated pathway after enhanced release of dopamine in the NAcc on EtOH administration during EtOH conditioning. image We revealed signal transduction pathways that may promote sensitization of ethanol (EtOH)‐induced place preference. EtOH facilitated the release of dopamine (DA) in the Nucleus accumbens (NAcc), enhancing calcineurin function via dopamine D1‐like and D2‐like receptor activation, which in turn resulted in increased NFATc4 expression. Increase in NFATc4 may further facilitate transcription factor binding to IP3R‐1 promoter domain to stimulate IP3R‐1 synthesis. Such increased IP3R‐1 elevates intracellular Ca2+ concentration via facilitated mobilization of Ca2+ from the intracellular Ca2+ stores to the cytosol.

AbstractAlcohol engages signaling pathways in the brain. Midkine (MDK) is a neurotrophic factor that is over‐expressed in the prefrontal cortex of alcoholics.MDKand one of its receptors, anaplastic lymphoma kinase (ALK), also regulate behavioral responses to ethanol in mice. The goal of this study was to determine whetherMDKandALKexpression and signaling are activated by ethanol. We found that ethanol treatment of neuroblastoma cells increasedMDKandALKexpression. We also assessed activation ofALKby ethanol in cells and found thatALKandALK‐dependent extracellular signal‐regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) phosphorylation increased rapidly with ethanol exposure. Similarly, treatment of cells with recombinantMDKprotein increasedALK,ERKand STAT3 phosphorylation, suggesting that ethanol may utilizeMDKto activateALKsignaling. In support of this, transfection of cells withMDKsiRNAs attenuatedALKsignaling in response to ethanol. Ethanol also activatesERKsignaling in the brain. We found that inhibition ofALKor knockout ofMDKattenuated ethanol‐inducedERKphosphorylation in mouse amygdala. These results demonstrate that ethanol engagesMDKandALKsignaling, which has important consequences for alcohol‐induced neurotoxicity and the regulation of behaviors related to alcohol abuse.imageWe propose that ethanol (a) increases transcription of the anaplastic lymphoma kinase (ALK) and midkine (MDK) genes and (b) rapidly activates extracellular signal‐regulated kinase (pERK1/2) and signal transducer and activator of transcription 3 (pSTAT3) through MDK and ALK. Activation of ALK and MDK signaling by ethanol may alter behavioral responses to ethanol with implications for the development of alcohol use disorders.

Abstract: Repeated amphetamine administration to rats under chronic ethanol intoxication resulted in the formation of 1,3‐dimethyl‐1,2,3,4‐tetrahydroisoquinoline (1,3‐DiMeTIQ), a novel metabolite of amphetamines. 1,3‐DiMeTIQ was quantified with a sensitive, specific assay using gas chromatography‐mass spectrometry. It was not found in the brains of rats given repeated amphetamine administration but no ethanol. The chronic ethanol‐intoxicated rats subjected to repeated amphetamine administration exhibited behavioral abnormalities, such as repeated convulsions and curving of the back. 1,3‐DiMeTIQ contents were markedly higher in the brain or plasma of rats manifesting abnormal behavior in comparison with those in rats behaving normally. Thus, the 1,3‐DiMeTIQ content in the rat brain seems to have some relationship with behavioral abnormalities. This study also confirmed that 1,3‐DiMeTIQ can cross the blood‐brain barrier in the rat. Intraperitoneal 1,3‐DiMeTIQ injections to rats caused behavioral symptoms similar to those observed in rats with chronic ethanol intoxication and repeated amphetamine administration. The effect of toxic doses of 1,3‐DiMeTIQ on dopaminergic and serotonergic metabolism in the whole rat brain was also investigated.

Abstract: The effect of acute ethanol administration on histamine (HA) dynamics was examined in the mouse hypothalamus. The steady‐state level of HA did not change after intraperitoneal administration of ethanol (0.5–5 g/kg), whereas the level of tele‐methylhistamine (t‐MH), a predominant metabolite of brain HA, increased when 3 and 5 g/kg of ethanol was given. Pargyline hydrochloride (80 mg/kg, i.p.) increased the level of t‐MH by 72.2% 90 min after the treatment. Ethanol at any dose given did not significantly affect the t‐MH level in the pargyline‐pretreated mice. Decrease in the t‐MH level induced by metoprine (10 mg/kg, i.p.), an inhibitor of HA‐N‐methyltransferase, was suppressed by ethanol (5 g/kg), thereby suggesting inhibition of the elimination of brain t‐MH. Ethanol (5 g/kg) significantly delayed the depletion of HA induced by (S)‐α‐fluoromethylhistidine (50 mg/kg, i.v.), a specific inhibitor of histidine decarboxylase. Therefore, a large dose of ethanol apparently decreases HA turnover in the mouse hypothalamus.

The use of cortical slices in the study of cerebral metabolism permits a wide range of experimentation, and yields information not readily obtainable from in situ preparations. The incubation media principally employed for such in vitro systems have been variations of the Krebs‐Ringer solutions (Krebs and Henseleit, 1932; Mcilwain,1959a; Heald, 1960). Although capable of supporting adequate respiration of the separated tissue, such media do not sustain all metabolic responses comparable to in vivo conditions (Mcilwain, 1959b). This paper is concerned with the effects of added creatine and ethanolamine on the metabolism of their phosphates in rabbit cerebral cortex slices in vitro. These compounds were chosen because of the sensitivity of phosphoryl creatine to metabolic deficiency as well as its important involvement in energy metabolism, and because of the rather wide‐spread presence of phosphoryl ethanolamine in animal tissues (Shaw, 1955; Long, 1961; Cohen and Lin, 1962). Some experiments were also done with slices from very young rabbits for comparative purposes.

Abstract— The enzymes catalysing ethanol metabolism, alcohol dehydrogenase (EC 1.l.1.1) and aldehyde dehydrogenase (EC 1.2.1.3), were assayed in a variety of neural and somatic tissues of the rat, the human counterparts of which are known to be vulnerable to excessive ethanol. The activity of alcohol dehydrogenase was assayed by the coupled oxidation of ethanol and reduction of lactaldehyde, a method which we have recently found to be sufficiently sensitive and specific to measure the relatively low levels of activity in whole brain. Detectable activities of these enzymes were found in peripheral nerve, skeletal muscle, retina, optic nerve and various regions of brain, as well as in a variety of non‐neural tissues. The levels of the enzymic activities in all tissues were markedly lower than those of liver, but probably sufficient to perform a local function in the metabolism of ethanol or other endogenous substrates. The activity of alcohol dehydrogenase in the various tissues, like that of liver, was confined to the cytosol and exhibited kinetic properties and responses to inhibitors almost identical to those of the liver enzyme. We consider the results to be consistent with the hypothesis that the pathological effects of alcohol may be related, at least in part, to local mechanisms for the metabolism of alcohol.

Abstract— The activities of 7 enzymes (hexokinase, phosphofructokinase, glucose‐6‐P dehydrogenase, 6‐P‐gluconic dehydrogenase, NADP linked isocitric dehydrogenase, malic dehydrogenase and lactic dehydrogenase) were measured in individual nerve cell bodies of 8 different neuronal types: pyramidal cells from cerebral cortex and Amnion's horn, Purkinje cells, giant cells in the reticular formation, Deiters’nucleus cells, facial nucleus cells, anterior horn cells and dorsal root ganglion cells. Samples of similar size were analysed from the molecular layer of cerebellum.The cell bodies were dissected from frozen‐dried tissue sections and weighed on quartz fibre balances. The weights ranged from 0–2 ng for the smallest pyramidal cells to 9 ng for the largest giant cells. The specific enzymatic reactions were carried out in small volumes (0–01–5 μl) under mineral oil (‘oil‐well technique’). The NADPH2 or NAD formed was amplified by‘enzymatic cycling’and measured fluorometrically. A new cycling method was used for measuring the NAD formed in three of the enzymatic methods. Double cycling was used to measure glucose‐6‐P and 6‐P‐gluconate dehydrogenases in the smallest cell bodies.Each type of neuron exhibited a unique enzyme pattern, but four general patterns could be distinguished. The most variable of the enzymes was glucose‐6‐P dehydrogenase which was nearly 10‐fold higher in anterior horn cells than in pyramidal cells from the cerebral cortex. Malic dehydrogenase was the most constant, with a 3‐fold range from the highest (Purkinje cells) to the lowest (dorsal root ganglion cells).

Abstract— Effects of the acute and chronic administration of ethanol have been investigated in mouse brain on the redox‐state, citric acid cycle function, levels of adenine nucleotides and other metabolites. Cerebral oxidation of ethanol, activity of alcohol dehydrogenase and the permeability of brain and liver mitochondrial preparations after chronic ethanol administration have been also investigated. Acute or chronic administration of ethanol resulted in a small but significant increase in the reduced components of certain dehydrogenase‐linked substrate pairs in brain. Pyrazole, an inhibitor of alcohol dehydrogenase, prevented the ethanol‐induced changes in brain. 14CO2 production from several substrates was inhibited in brains from chronically ethanol‐fed animals. Addition of pyrazole, however, prevented the ethanol‐mediated inhibition of 14CO2 production. Chronic administration of ethanol resulted in decreased levels of ATP and creatine phosphate in the brain, and increased contents of ADP and AMP. The cerebral activities of alcohol dehydrogenase and succinic dehydrogenase, oxidation of ethanol, mitochondrial oxidation of a‐glycerophosphate, and levels of NADH remained unaffected by the chronic administration of ethanol. In contrast to liver, where chronic administration of ethanol increased the contribution of 'substrate shuttles’resulting in increased oxidation of ethanol; in brain, the contribution of these 'shuttles’remained unaffected.