title: Chronic treatment and withdrawal of the cannabinoid agonist WIN 55,212-2 modulate the sensitivity of presynaptic receptors involved in the regulation of monoamine syntheses in rat brain.
abstract: Brain monoamines are involved in many neurochemical and behavioral effects of cannabinoids, but little is known on the regulation of noradrenaline, dopamine, and serotonin (5-HT) synthesis in cannabinoid addiction. This study investigated in rat brain the chronic effects of the potent cannabinoid agonist WIN 55,212-2 and of rimonabant-precipitated withdrawal, as well as the sensitivity of synthesis-modulating inhibitory receptors, on the accumulation of L-3,4-dihydroxyphenylalanine (DOPA) and 5-HTP after decarboxylase inhibition. Acute WIN (8 mg/kg; 1 h) increased DOPA synthesis in cortex (52%), hippocampus (51%), and cerebellum (56%) and decreased DOPA accumulation in striatum (31%). Acute WIN also decreased the synthesis of 5-HTP in all brain regions (40-53%). Chronic WIN (2-8 mg/kg; 5 days) and/or antagonist-precipitated withdrawal induced tolerance to the acute effects of WIN on the accumulation of DOPA (cortex and striatum) and 5-HTP (all brain regions). The inhibitory effect of clonidine (alpha2-agonist; 1 mg/kg) on the accumulation of DOPA (15-41%) and 5-HTP (22-41%) was markedly decreased or abolished after chronic WIN and precipitated withdrawal, mainly in noradrenergic and serotonergic brain regions, which indicated desensitization of alpha2-autoreceptors and alpha2-heteroreceptors regulating the synthesis of noradrenaline and 5-HT. In WIN-dependent rats (chronic and withdrawal states), the effect of a low dose of (+/-)-8-hydroxy-2-(di-n-propylamino)-tetralin (5-HT1A agonist; 0.1 mg/kg) on the accumulation of precursor amino acids was markedly potentiated in cerebellum and striatum, indicating the induction of supersensitivity of 5-HT1A-autoreceptors and 5-HT1A-heteroreceptors that regulate the synthesis of 5-HT, noradrenaline, and dopamine in these brain regions. These chronic adaptations in presynaptic receptor function could play a relevant role in cannabinoid addiction.
authors: Laboratori de Neurofarmacologia, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Cra. Valldemossa km 7.5, 07122, Palma de Mallorca, Spain.
authors: David
authors: D
authors: Moranta
authors: Susana
authors: S
authors: Esteban
authors: Jesús A
authors: JA
authors: García-Sevilla
mesh_terms: D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000378:metabolism; D048588:Benzoxazines / Q000009:adverse effects*; D015306:Biogenic Monoamines / Q000096:biosynthesis*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D063386:Cannabinoid Receptor Agonists; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009025:Morpholines / Q000009:adverse effects*; D009281:Naphthalenes / Q000009:adverse effects*; D009638:Norepinephrine / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000096:biosynthesis; D058825:Serotonin 5-HT1 Receptor Agonists; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D017660:Autoreceptors; D048588:Benzoxazines; D015306:Biogenic Monoamines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D058825:Serotonin 5-HT1 Receptor Agonists; D012701:Serotonin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D004295:Dihydroxyphenylalanine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006916:5-Hydroxytryptophan; D009638:Norepinephrine