EVIDENCE THAT LITHIUM INDUCES A GLUTAMATERGIC - NITRIC OXIDE-MEDIATEDRESPONSE IN RAT-BRAIN

Studies have indicated the involvement of a glutamatergic mechanism in lithium (Li+) action. Glutamatergic agonists, such as kainic acid, ar e known to promote the synthesis of nitric oxide (NO) and to increase cGMP, while Li+ has displayed a similar, yet unexplained, ability to i ncrease cGMP. NO synthesis is regarded as the principal prodromal even t leading to the activation of the guanyl cyclase-cGMP transduction me chanism. In the present study, the involvement of the NO:cGMP pathway in the action of Li+ was examined, while the possibility of a glutamat ergic mechanism in this response was also investigated. Parameters exa mined 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 a nd NO2- data throughout all the groups. Chronic treatment of rats with LiCl (0.30% m/m) engendered a significant increase in cGMP levels whi ch was inhibited by the NO-synthase (NOS) inhibitor, N-nitro-L-arginin e 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 o n cortical NO2- was observed in the combination of LiCl and kainic aci d. Collectively, these data implicate an involvement of a glutamatergi c-mediated NO:cGMP transduction mechanism in the action of Li+.