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.

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.