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Regulation of Brain Anandamide by Acute Administration of Ethanol

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Regulation of Brain Anandamide by Acute Administration of Ethanol Biochem. J. (2007) 404, 97–104 (Printed in Great Britain) doi:10.1042/BJ20061898 97 Regulation of brain anandamide by acute administration of ethanol Belen FERRER*†, Francisco Javier BERMUDEZ-SILVA*,´ Ainhoa BILBAO*‡, Lily ALVAREZ-JAIMES§, Irene SANCHEZ-VERA*, Andrea GIUFFRIDA†1, Antonia SERRANO*, Elena BAIXERAS*, Satishe KHATURIA†, Miguel NAVARRO‡, Loren H. PARSONS§, Daniele PIOMELLI†2 and Fernando RODR´IGUEZ DE FONSECA*‡2 *Fundacion´ IMABIS, Hospital Carlos Haya, Malaga´ 29010, Spain, †Department of Pharmacology, University of California, Irvine, CA, 92697-4625, U.S.A., ‡Departamento de Psicobiolog´ıa, Universidad Complutense, Madrid 28224, Spain, and §Molecular and Integrative Neuroscience Department, The Scripps Research Institution. La Jolla, CA 92037, U.S.A. The endogenous cannabinoid acylethanolamide AEA (arachi- bens. There were no changes in the expression and enzymatic donoylethanolamide; also known as anandamide) participates in activity of the main enzyme that degrades AEA, the fatty acid the neuroadaptations associated with chronic ethanol exposure. amidohydrolase. Acute ethanol administration did not change However, no studies have described the acute actions of ethanol either the activity of N-acyltransferase, the enzyme that catalyses on AEA production and degradation. In the present study, we the synthesis of the AEA precursor, or the expression of NAPE- investigated the time course of the effects of the intraperitoneal PLD (N-acylphosphatidylethanolamine-hydrolysing phospholi- administration of ethanol (4 g/kg of body mass) on the endo- pase D), the enzyme that releases AEA from membrane phospho- genous levels of AEA in central and peripheral tissues. Acute lipid precursors. These results suggest that receptor-mediated ethanol administration decreased AEA in the cerebellum, the release of acylethanolamide is inhibited by the acute adminis- hippocampus and the nucleus accumbens of the ventral striatum, tration of ethanol, and that this effect is not derived from increased as well as in plasma and adipose tissue. Parallel decreases of fatty acid ethanolamide degradation. a second acylethanolamide, PEA (palmitoylethanolamide), were observed in the brain. Effects were observed 45–90 min after eth- anol administration. In vivo studies revealed that AEA decreases Key words: alcohol, anandamide, arachidonoylethanolamide were associated with a remarkable inhibition of the release (AEA), cannabinoid, fatty acid amidohydrolase (FAAH), hip- of both anandamide and glutamate in the nucleus accum- pocampus. INTRODUCTION [12,13] or FAAH (fatty acid amidohydrolase) [14], the enzyme responsible for AEA inactivation [15], have been described. Several research lines have established a role for both the eCB Despite the extensive information on the effects of chronic (endocannabinoid) AEA (arachidonoylethanolamide or anandam- exposure to alcohol, no information is available on the acute ide) and the CB1 (cannabinoid 1) receptor in ethanol-dependence effects of ethanol on AEA formation and degradation. We [1–3]. While administration of CB1 receptor agonists promotes have addressed this issue by analysing the time course of the ethanol intake [4], the administration of a CB1 receptor anta- effects of acute ethanol on AEA and the related mediator PEA gonist decreases ethanol self-administration [5], especially in (palmitoylethanolamide) formation in the brain. We selected three animals with a history of ethanol-dependence [6] or in alcohol- different brain areas characterized by the sensitivity to ethanol preferring rat lines [7]. Following these findings, CB1-receptor- effects: the nucleus accumbens, where intrinsic neurons and knockout mice were found to display decreased ethanol pre- glutamate release are inhibited by ethanol [16,17]; the dorsal ference, a phenotype that resembled that of wild-type litter- hippocampus, where ethanol inhibits acetylcholine release [18], as mates treated with a CB1 receptor antagonist [3]. well as glutamate release and glutamate-dependent depolarization Molecular studies have shown that chronic ethanol admini- [19–21]; and the cerebellum, where ethanol modifies the firing stration is associated with an increased formation of both pattern and the glutamate response of Purkinje neurons [22]. AEA and its membrane precursor N-arachidonoyl phosphatidy- These brain areas display relevant densities of CB1 receptors lethanolamine [8]. Chronic alcohol exposure also resulted in where they participate in presynaptic control of neurotransmitter stimulation of 2-arachidonoylglycerol, a second eCB [9]. Animal release [23–26]. We also monitored the in vivo and in vitro studies also revealed that chronic exposure to ethanol down- actions of ethanol on the enzymatic activities of NAT (N- regulated CB1 receptors in the brain [10]. Finally, a gene-screening acyltransferase) and FAAH, enzymes involved in AEA formation study has identified the CB1 receptor as one of the genes whose and degradation [15,27,28], as well as the mRNA expression of expression is permanently affected by serial cycles of ethanol- the NAPE-PLD (N-acylphosphatidylethanolamine-hydrolysing dependence and -withdrawal [11]. These data indicate a role for phospholipase D), the recently cloned enzyme that cleaves AEA the eCB system as a relevant contributor to alcoholism. Human from its membrane precursor [29]. The results suggest that acute genetic studies support this experimental hypothesis, since a administration of ethanol markedly inhibits in vivo formation of linkage between clinical forms of alcoholism and polymorphisms AEA and its related eCB PEA in the rat brain, and that this effect and/or mutations of the genes encoding either the CB1 receptor is not dependent on the activity of FAAH or NAT enzymes. Abbreviations used: aCSF, artificial cerebrospinal fluid; AEA, arachidonoylethanolamide; CB1, cannabinoid 1; eCB, endocannabinoid; FAAH, fatty acid amidohydrolase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GUS, β-glucuronidase; HB-β-CD, hydroxypropyl-β-cyclodextrin; NAPE-PLD, N- acylphosphatidylethanolamine-hydrolysing phospholipase D; NAT, N-acyltransferase; PEA, palmitoylethanolamide; PLD, phospholipase D. 1 Present address: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, U.S.A. 2 Correspondence may be addressed to either of these authors (email [email protected] or [email protected]). c The Authors Journal compilation c 2007 Biochemical Society 98 B. Ferrer and others MATERIALS AND METHODS accumbens, dorsal hippocampus and cerebellum were dissected as described above. Animals + Male Wistar rats (Charles River Laboratories), weighing 350 − Plasma ethanol levels 50 g, were housed individually with food and water available ad libitum. Animals were kept in a standard 12 h light/12 h dark Plasma ethanol levels were measured enzymatically using a photoperiod (lights on 08:00 h–20:00 h). They were handled daily commercial kit (Sigma). Assays were run following the manu- for 1 week before starting the experiments, and they received facturer’s instructions. intraperitoneal saline injections once a day in the 3 days that preceded the experimental administration of ethanol. All animal HPLC–MS analyses of tissue contents of acylethanolamides procedures met the National Institutes of Health guidelines AEA and PEA were solvent-extracted from plasma, brain areas for the care and use of laboratory animals, and the European (nucleus accumbens, dorsal hippocampus and cerebellum) and Communities directive 86/609/EEC regulating animal research. peripheral tissues (perirenal fat, liver and ileum), fractionated by column chromatography and quantified by HPLC–MS with an Chemicals isotope-dilution method [30,34]. 2 Unlabelled AEA and PEA standards and H4-labelled AEA and PEA were synthesized as described in [30]. 1,2-Di[14C]palmitoyl- Real-time PCR for relative quantification of CB1 receptor, FAAH, sn-glycerophosphocholine (108 mCi/mmol) was purchased from NAPE-PLD and GAPDH (glyceraldehyde 3-phosphate Amersham Biosciences, and [1-3H]ethanolamine hydrochloride dehydrogenase) mRNA expression (60 Ci/mmol) was from American Radiolabeled Chemicals. Total RNA from nucleus accumbens, hippocampus and cere- bellum was obtained using TRIzol® reagent (Gibco BRL Life Technologies) according to the manufacturer’s instructions. All Vehicle and ethanol administration: blood and tissue sampling RNA samples showed A260/A280 ratios between 1.8 and 2.0. Ethanol was dissolved in sterile 0.9% (w/v) saline (NaCl) before First-strand synthesis from each sample was done using random intraperitoneal injection. Rats received either 15% (w/v) ethanol hexamer primer and MMLV (Moloney murine leukaemia virus) solution (0.75, 2 or 4 g/kg of body mass) or a similar volume reverse transcriptase (Roche Applied Science) according to the of a 0.9% saline solution (control group). In order to avoid poten- manufacturer’s instructions. Negative-control reactions omitted tial circadian variations on eCB levels, as described previously reverse transcriptase. Resulting cDNAs were used as the template [31], all the experiments took place between 09:00 h and 13:00 h for real-time quantitative PCR, which was performed using the during the light phase of the cycle. Since it has been described LightCycler instrument (Roche) with the SYBR Green I detection that restraint stress may affect brain AEA levels in specific format. brain areas [32], we first explored the potential effects of the The following primers were used
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