Evidence that lithium induces a glutamatergic: nitric oxide-mediated response in rat brain.
Studies have indicated the involvement of a glutamatergic mechanism in lithium (Li+) action. Glutamatergic agonists, such as kainic acid, are known to promote the synthesis of nitric oxide (NO) and to increase cGMP, while Li+ has displayed a similar, yet unexplained, ability to increase cGMP. NO synthesis is regarded as the principal prodromal event leading to the activation of the guanyl cyclase-cGMP transduction mechanism. In the present study, the involvement of the NO:cGMP pathway in the action of Li+ was examined, while the possibility of a glutamatergic mechanism in this response was also investigated. Parameters examined included cortical accumulation of cGMP and the stable oxidative metabolites of NO, viz. NO2- and NO3-, collectively expressed as NO2-. A significant positive correlation was observed in the in vivo cGMP and NO2- data throughout all the groups. Chronic treatment of rats with LiCl (0.3% m/m) engendered a significant increase in cGMP levels which was inhibited by the NO-synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME). Acute administration of kainic acid resulted in an increased accumulation of NO2-, also prevented by concomitant L-NAME administration. In addition, a synergistic stimulatory response on cortical NO2- was observed in the combination of LiCl and kainic acid. Collectively, these data implicate an involvement of a glutamatergic-mediated NO:cGMP transduction mechanism in the action of Li+.
Harvey
B H
BH
Department of Chemical Pathology, University of Stellenbosch Medical School, Tygerberg, South Africa.
Carstens
M E
ME
Taljaard
J J
JJ
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004327:Drinking Behavior / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D011141:Polyuria; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects
D005971:Glutamates; D009569:Nitric Oxide; D001120:Arginine; D018021:Lithium Chloride; D006152:Cyclic GMP; D007608:Kainic Acid; D019331:NG-Nitroarginine Methyl Ester