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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

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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 (α2-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 α2-autoreceptors and α2-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.

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Acknowledgments

This study was supported by grants SAF2004-03685 and SAF2008-01311 (Programa Nacional de Biomedicina, MEC and FEDER, Madrid, Spain), FIS PI05-0353 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, MSC, Madrid, Spain), and Delegación del Gobierno para el Plan Nacional sobre Drogas (project 2007/032, MSC, Madrid, Spain). The research was also funded in part by Red Temática de Investigación Cooperativa en Salud (RETICS, Instituto de Salud Carlos III, MSC, Madrid): Red de Trastornos Adictivos, Grupo RD06/001/003. D.M. was supported by a predoctoral fellowship from MEC (Madrid, Spain). The authors thank Sanofi-Synthélabo (Montpellier, France) for the gift of SR141716A (rimonabant). J.A.G.-S. is a member of the Institut d’Estudis Catalans (Barcelona, Catalonia, Spain).

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  1. 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

    David Moranta, Susana Esteban & Jesús A. García-Sevilla

  2. Red Temática de Investigación Cooperativa en Salud sobre Trastornos Adictivos, Madrid, Spain

    David Moranta, Susana Esteban & Jesús A. García-Sevilla

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  1. David Moranta
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Moranta, D., Esteban, S. & García-Sevilla, J.A. 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. Naunyn-Schmied Arch Pharmacol 379, 61–72 (2009). https://doi.org/10.1007/s00210-008-0337-0

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