Lithium modulation of cortical cyclic nucleotides: evidence for the Yin-Yang hypothesis

Rats were subjected to chronic treatment with lithium chloride (0.2-0.3%) over a period of 3 weeks. The activity of cortical phosphodiesterase (EC 3.1.4.17) was determined simultaneously with cyclic AMP and cyclic GMP content and compared to control, untreated animals. Lithium, at therapeutic serum concentrations was found to suppress cyclic AMP levels with a concomitant increase in cyclic AMP-phosphodiesterase activity. A simultaneous two-fold increase in cyclic GMP was observed. Through the alteration of cortical cholinergic activity with physostigmine and the use of cyclic GMP as a cholinergic marker, we were able to demonstrate a novel cholinotropic property of lithium to stimulate synthesis of cyclic GMP. This effect appears to be linked, in a Yin-Yang mechanism, to the observed suppression of cyclic AMP induced by lithium through activation of cyclic AMP-phosphodiesterase.