INFLUENCE OF CANNABINOIDS ON ELECTRICALLY-EVOKED DOPAMINE RELEASE ANDCYCLIC-AMP GENERATION IN THE RAT STRIATUM

Using the endogenous cannabinoid receptor agonist anandamide, the synt hetic agonist CP 55940 {[1 alpha,2 beta(R)5 -[5-hydroxy-2-(3-hydroxypr opyl)cyclohexyl]phenol}, and the specific antagonist SR 141716 [N-(pip eridin-1-yl)-5-(4-chlorophenyl)-1 dichlorophenyl)-4-methyl-1H-pyrazole -3-carboxamide hydrochloride], second messenger activation of the cent ral cannabinoid receptor (CB1) was examined in rat striatal and cortic al slices. The effects of these cannabinoid ligands on electrically ev oked dopamine (DA) release from [H-3]dopamine-prelabelled striatal sli ces were also investigated. CP 55940 (1 mu M) and anandamide (10 mu M) caused significant reductions in forskolin-stimulated cyclic AMP accu mulation in rat striatal slices, which were reversed in the presence o f SR 141716 (1 mu M). CP 55940 (1 mu M) had no effect on either KCl- o r neurotransmitter-stimulated H-3-inositol phosphate accumulation in r at cortical slices. CP 55940 and anandamide caused significant reducti ons in the release of dopamine after electrical stimulation of [H-3]do pamine-prelabelled striatal slices, which were antagonised by SR 14171 6. SR 141716 alone had no effect on electrically evoked dopamine relea se from rat striatal slices, These data indicate that the CB1 receptor s in rat striatum are negatively linked to adenylyl cyclase and dopami ne release, That the CB1 receptor may influence dopamine release in th e striatum suggests that cannabinoids play a modulatory role in dopami nergic neuronal pathways.