title: Ethanol desensitizes cannabinoid CB1 receptors modulating monoamine synthesis in the rat brain in vivo.
abstract: The endocannabinoid system and the cannabinoid CB(1) receptors are involved in the development of ethanol tolerance and dependence. This study aimed to investigate the in vivo sensitivity of a CB(1) receptor agonist (WIN 55,212-2) modulating the synthesis of 3,4-dihydroxy-phenylalanine/dopamine/noradrenaline (DOPA/DA/NA) and that of 5-hydroxy-tryptophan/serotonin (5-HTP/5-HT) in rat brain after ethanol treatment and withdrawal. In control rats, WIN 55,212-2 (4 mg/kg, i.p., for 1h), through a mechanism sensible to the CB(1) antagonist SR 141716A, increased the synthesis of DOPA/NA in a slice of brainstem containing the locus ceruleus (250%) and in the hippocampus (64%), and it reduced DOPA/DA synthesis in the striatum (47%). WIN 55,212-2 also decreased the synthesis of 5-HTP/5-HT in the locus ceruleus (43%), hippocampus (35%) and striatum (35%). In the locus ceruleus of ethanol-treated rats, the stimulatory effect of WIN 55,212-2 on DOPA/NA synthesis was abolished (acute treatment) or markedly attenuated (53-55%, chronic treatment and withdrawal), whereas in the hippocampus this effect was reduced only in chronic ethanol-withdrawn rats (33%). In the striatum of ethanol-treated rats (acute, chronic and withdrawal), the inhibitory effect of WIN 55,212-2 on DOPA/DA synthesis was completely blunted or markedly reduced. Similarly, the inhibitory effect of WIN 55,212-2 on 5-HTP/5-HT synthesis was reduced or abolished in the three brain regions after chronic ethanol and during withdrawal. These results indicate that treatment with ethanol in rats induces a functional desensitization of CB(1) receptors modulating the synthesis of brain monoamines.
authors.affiliation: Laboratori de Neurofarmacologia, Institut Universitari d'Investigació en Ciències de la Salut, IUNICS, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Moranta
authors.forename: Susana
authors.initials: S
authors.lastname: Esteban
authors.forename: Jesús A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D006916:5-Hydroxytryptophan / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage*; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*
chemical_list: D048588:Benzoxazines; D015306:Biogenic Monoamines; D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D006834:Hydrazines; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D015102:3,4-Dihydroxyphenylacetic Acid; D000431:Ethanol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C004297:3-hydroxybenzylhydrazine; D006916:5-Hydroxytryptophan