Cannabinoid CB 1 receptor‐mediated modulation of evoked dopamine release and of adenylyl cyclase activity in the human neocortex

The present study investigated the binding characteristics of various ligands to cannabinoid CB 1 receptors in human neocortex and amygdala. In addition, the functionality of CB 1 receptors in the human neocortex was assessed by examining the effects of CB 1 receptor ligands on evoked [ 3 H]‐dopamine (DA) release in superfused brain slices and on synaptosomal cAMP accumulation. Saturation‐binding assays in human neocortical and amygdala synaptosomes using a radiolabelled cannabinoid receptor agonist ([ 3 H]‐CP55.940) revealed p K d values of 8.96 and 8.63, respectively. The numbers of binding sites ( B max ) were 3.99 and 2.67 pmol (mg protein) −1 , respectively. Various cannabinoid receptor ligands inhibited [ 3 H]‐CP55.940 binding with rank order potencies corresponding to those of previous studies in animal tissues. Electrically evoked [ 3 H]‐DA release from human neocortical slices was inhibited by CP55.940 (IC 50 6.76 n M , I max 65%) and strongly enhanced by the cannabinoid receptor antagonist AM251. However, [ 3 H]‐DA release was not influenced in rat neocortex. In human tissue, the estimated endocannabinoid concentration in the biophase of the release‐modulating CB 1 receptors was 1.07 n M , expressed in CP55.940 units. K + ‐evoked [ 3 H]‐DA release in the presence of tetrodotoxin (TTX) was strongly inhibited by CP55.940 in humans, but not in rats. In human tissue, CP55.940 inhibited forskolin‐stimulated cAMP accumulation (IC 50 20.89 n M , I max 35%). AM251 blocked this effect and per se increased forskolin‐stimulated cAMP accumulation by ∼20%. In conclusion, cannabinoids modulate [ 3 H]‐DA release and adenylyl cyclase activity in the human neocortex. CB 1 receptors are located on dopaminergic nerve terminals and seem to be tonically activated by endocannabinoids.British Journal of Pharmacology (2004) 141 , 1193–1203. doi: 10.1038/sj.bjp.0705706