GABA-like actions of levonantradol.
The interaction of levonantradol and its pharmacologically less active (+)-enantiomer with GABAergic mechanisms was studied in several in vivo systems: (1) rat cerebellar cGMP, based on the inverse relationship of GABAergic activity and cGMP levels; (2) convulsions elicited by 3-mercaptopropionic acid, an inhibitor of GABA synthesis; and (3) activated dopamine synthesis in rat striatum following blockade of dopamine receptors. Levonantradol decreased rat cerebellar cGMP content at low doses (1.0 mg/kg intraperitoneally) and antagonized elevation of cGMP levels by the GABA biosynthesis inhibitor isoniazid at even lower doses (0.32 mg/kg intraperitoneally); this activity pattern is suggestive of GABAergic activity. This conclusion is also supported by levonantradol's protection of mice against the convulsant effects of 3-mercaptopropionic acid, GABAergic agents are known to antagonize the enhanced dopamine synthesis and turnover that accompany dopamine receptor blockade by neuroleptics. Levonantradol (0.047 mg/kg intravenously) stereospecifically attenuated the elevated dopa accumulation induced by haloperidol. Levonantradol is at least 100-fold more active than THC in blocking isoniazid-induced elevation of cGMP levels in rat cerebellum or haloperidol-induced enhanced dopa accumulation in rat striatum.
D015097:3-Mercaptopropionic Acid / Q000037:antagonists & inhibitors; D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D006220:Haloperidol / Q000037:antagonists & inhibitors; D008297:Male; D010617:Phenanthridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology*
D010617:Phenanthridines; D005680:gamma-Aminobutyric Acid; D004295:Dihydroxyphenylalanine; C025490:nantradol; D015097:3-Mercaptopropionic Acid; D006152:Cyclic GMP; D006220:Haloperidol