piperidines and delta(9-11)-tetrahydrocannabinol

1. 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. 2. Saturation-binding assays in human neocortical and amygdala synaptosomes using a radiolabelled cannabinoid receptor agonist ([(3)H]-CP55.940) revealed pK(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. 3. Various cannabinoid receptor ligands inhibited [(3)H]-CP55.940 binding with rank order potencies corresponding to those of previous studies in animal tissues. 4. Electrically evoked [(3)H]-DA release from human neocortical slices was inhibited by CP55.940 (IC(50) 6.76 nm, 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 nm, expressed in CP55.940 units. 5. K(+)-evoked [(3)H]-DA release in the presence of tetrodotoxin (TTX) was strongly inhibited by CP55.940 in humans, but not in rats. 6. In human tissue, CP55.940 inhibited forskolin-stimulated cAMP accumulation (IC(50) 20.89 nm, I(max) 35%). AM251 blocked this effect and per se increased forskolin-stimulated cAMP accumulation by approximately 20%. 7. 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.

Topics: Adenylyl Cyclases; Amygdala; Animals; Arachidonic Acids; Benzoxazines; Binding Sites; Colforsin; Cyclic AMP; Cyclohexanols; Dopamine; Dronabinol; Electric Stimulation; Endocannabinoids; Female; Humans; Ligands; Male; Morpholines; Naphthalenes; Neocortex; Piperidines; Polyunsaturated Alkamides; Potassium; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Synaptosomes; Tetrodotoxin; Tritium

The effects of acute and repeated administration of Delta9-tetrahydrocannabinol (Delta9-THC), the psychoactive principle of marijuana, on acetylcholine release in the hippocampus was studied in freely moving rats by microdialysis. The acute intraperitoneal (i.p.) administration of Delta9-THC at the doses of 2.5 and 5 mg/kg reduced acetylcholine release by about 25% and 45%, respectively. A dose of 7.5 mg/kg produced no further reduction. Delta9-THC effects were antagonized by the cannabinoid CB1 antagonist SR141716A at the i.p. dose of 1 mg/kg, per se ineffective in modifying acetylcholine concentrations. After a repeated exposure (twice daily for up to seven days) to Delta9-THC (7.5 mg/kg, i.p.) or vehicle (0.3 ml/kg, i.p.), the inhibitory effect of Delta9-THC (2.5 and 5 mg/kg, i.p) on acetylcholine release was not reduced. The results confirm previous observations that cannabinoids inhibit acetylcholine release through cannabinoid CB1 receptors, and indicate that no tolerance to this effects develops after a repeated Delta9-THC administration.

Topics: Acetylcholine; Animals; Brain Chemistry; Cannabinoids; Cognition; Dronabinol; Hippocampus; Male; Microdialysis; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant