ABSENCE OF AN EFFECT OF THE LITHIUM-INDUCED INCREASE IN CYCLIC-GMP ONTHE CYCLIC GMP-STIMULATED PHOSPHODIESTERASE (PDE-II) - EVIDENCE FOR CYCLIC AMP-SPECIFIC HYDROLYSIS

Chronic treatment of rats with LiCl is known to induce a decrease in c AMP, while this decrease has also been found to occur together with bo th a simultaneous increase in total cortical phosphodiesterase (PDE; E C 3.1.4.17) activity and a concomitant increase in cGMP. These studies have implicated an involvement of PDE in lithium (Li+) action and it has been suggested that cGMP and the cGMP-stimulated PDE may be instru mental in the observed effects of Li+ on cAMP. In this study, three is ozymes of PDE were isolated and identified from rat cortex and their a ctivity determined, together with simultaneous measurement of cAMP and cGMP, after chronic treatment with oral LiCl (0.35% m/m). Li+ treatme nt exerted profound effects on cyclic nucleotides in the cortex, induc ing significant suppression of cAMP while increasing cGMP levels. Howe ver, the ion only induced a slight but insignificant increase in the a ctivities of the three PDE isozymes. To confirm these observations, me thylparaben (MPB), a drug demonstrating both an ability to induce a se lective stimulation of cAMP-specific PDE and also to lower intracellul ar levels of cGMP, was co-administration orally (0.4% m/m) with Li+ ov er the same period. This combination emphasized certain actions of Li not noted with Li+ alone. MPB inhibited the Li+-induced increase in c GMP, yet did not prevent the ion from decreasing cAMP. However, the co mbination of Li+ and MPB engendered a synergistic 100% increase in the activity of the membrane-bound, cAMP-specific PDE, PDE IV. This combi nation also produced a significant suppression of cAMP, while no reduc tion in cGMP was observed. The data is indicative that Li+-induced sup pression of cAMP does not appear to be related to an effect on the cGM P-dependent PDE II, and that the increases in cGMP and PDE induced by Li+ observed previously and in the present study are two unrelated eve nts. Instead, the synergistic response of Li+ plus MPB on PDE IV, and the associated reduction of cAMP, indicate that Li+ may promote select ive cAMP hydrolysis via an effect on membrane-bound forms of PDE. This effect of Li+ on PDE IV, as well as the reciprocal effects on cyclic nucleotide balance, may have important implications in explaining the antipsychotic actions of the ion.