Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes
Howlett, A.C.; Fleming, R.M.
Molecular Pharmacology 26(3): 532-538
1984
ISSN/ISBN: 0026-895X PMID: 6092901 Document Number: 226554
Adenylate cyclase in plasma membranes was inhibited by .mu.mol concentrations of .DELTA.8-tetrahydrocannabinol and .DELTA.9-tetrahydrocannabinol [active ingredients of marihuana, a drug of abuse] and by levonantradol and desacetyllevonantradol. This inhibition was noncompetitive for stimulation of the enzyme at the prostanoid receptor by prostaglandin [PG] E1 or prostacyclin, or at the peptide receptor by secretin or vasoactive intestinal peptide. Forskolin-activated adenylate cyclase was also inhibited by cannabimimetic agents. Inhibition by cannabinoid compounds was neither synergistic nor additive with muscarinic or .alpha.-adrenergic agents when each was present at maximally inhibitory concentrations. Cannabinoid inhibition was not blocked by atropine, yohimbine or naloxone, suggesting that muscarinic, .alpha.2-adrenergic and certain opiate receptors may not be required for the response. The inhibition of adenylate cyclase was specific for psychoactive cannabinoids, since cannabinol and cannabidiol produced minimal or no response. Inhibition was also stereoselective, since dextronantradol did not produce the response. A biphasic log dose-response curve was observed for each of the cannabinoid drugs, such that reversal of the inhibition occurred at 3-10 .mu.M. Possible mechanisms for the effects of cannabinoid drugs on adenylate cyclase activity are discussed.