Cannabinoid CB1 receptor-mediated inhibition of NMDA- and kainate-stimulated noradrenaline and dopamine release in the brain

Guinea-pig hippocampal slices preincubated with [H-3]noradrenaline were sup erfused with medium containing desipramine and rauwolscine and rat striatal slices preincubated with [H-3]dopamine were superfused with medium contain ing nomifensine; the effect of cannabinoid receptor ligands on tritium over flow stimulated by NMDA or kainate was examined. Furthermore, the affinity of the drugs for cannabinoid CB1 receptors was determined in rat brain cort ex membranes using [H-3]SR 141716. In guinea-pig hippocampal slices preincubated with [H-3]noradrenaline, trit ium overflow stimulated by NMDA 100 mu M and 1000 mu M and by kainate 1000 mu M was inhibited by the cannabinoid receptor agonists CP-55,940 and/or WI N 55,212-2. The CB1 receptor antagonist SR 141716 increased the NMDA (1000 mu M)-stimulated tritium overflow but did not affect tritium overflow stimu lated by NMDA 100 mu M or kainate 1000 mu M. The inhibitory effect of WIN 5 5,212-2 on the NMDA ( 100 mu M)and kainate (1000 mu M)-evoked tritium overf low was antagonized by SR 141716. In rat striatal slices preincubated with [H-3]dopamine, WIN 55,212-2 Inhibited the NMDA (1000 mu M)-stimulated triti um overflow. SR 141716, which, by itself, did not affect tritium overflow, counteracted the inhibitory effect of WIN 55,212-2. [H-3]SR 141716 binding to rat cortical membranes was inhibited by SR 131716, CP-55,940 and WIN 55, 212-2 (pK(i) 8.53, 7.34 and 5.93, respectively) but not affected by desipr mine, rauwolscine and nomifensine (pK(i) < 5). In conclusion, activation of CB1 receptors inhibits the NMDA- and kainate-s timulated noradrenaline release in guinea-pig hippocampus and the NMDA-stim ulated dopamine release in rat striatum. The explanation for the facilitato ry effect of SR 131716 might be that it acts as an inverse agonist at CB1 r eceptors or that these receptors are activated by endogenous cannabinoids.