ACTIONS OF LITHIUM ON THE CYCLIC-AMP SIGNALING SYSTEM IN VARIOUS REGIONS OF THE BRAIN - POSSIBLE RELATIONS TO ITS PSYCHOTROPIC ACTIONS - A STUDY ON THE ADENYLATE-CYCLASE IN RATE CEREBRAL-CORTEX, CORPUS STRIATUM AND HIPPOCAMPUS

It has been estimated that in most industrialized countries 1 person o ut of every 1000 in the population is undergoing lithium treatment to stabilize their episodic mood disturbances due to manic-depressive ill ness. Lithium may stabilize mood swings by altering the action of cert ain neurotransmitters at the synaptic level in the brain. Recent resea rch suggests that lithium alters neurotransmission by affecting neurot ransmitter-coupled second messenger systems. A major second messenger system is the adenylate cyclase, which generates intracellular cAMP fr om ATP. The adenylate cyclases (type I-IV) are regulated by stimulator y and inhibitory receptors, which either stimulate or inhibit the aden ylate cyclase activity. The stimulatory and inhibitory neurotransmitte r-receptor signals are transferred to the catalytic unit of the adenyl ate cyclase by G(s) and G(i), respectively. The activated receptor ind uces GTP stimulation of the heterotrimeric G protein, leading to a dis sociation of the protein into the active alpha(GTP) and the beta gamm a complex. The former stimulates the catalytic unit of adenylate cycla se. The stimulation is terminated by a GTPase located on the ct subuni t that converts GTP to inactive GDP. At present, G proteins are known to play a central role in coupling receptors to effector proteins. In addition to extracellular regulation due to neurotransmitters, some ad enylate cyclases (type I, III) are regulated by CaM as a consequence o f enhanced intracellular concentrations of free Ca2+ The Ca2+-dependen tstimulation of adenylate cyclase by CaM is assumed to occur by a dire ct effect on the catalytic unit. The catalytic units sensitive to Ca2-CaM are also subjected to regulation by stimulatory and inhibitory ne urotransmitter stimuli. Magnesium is essential for adenylate cyclase a ctivity, since MgATP(2-) is the enzyme substrate. Furthermore, one Mg2 + site located on the G protein regulates both the receptor agonist af finity and the dissociation of the G protein during the activation cyc le, A second Mg2+ site on the catalytic unit is responsible for Mg2+ r egulation of the catalytic activity. The present work aimed at investi gating the mechanisms by which lithium in vitro and after chronic trea tment (ex vivo) affects adenylate cyclase activities in various region s of the rat brain. Lithium in vitro and ex vivo inhibited the selecti ve stimulation of adenylate cyclase by Ca2+-CaM in the cerebral cortex . Furthermore, lithium in vitro interacted directly with the catalytic unit of adenylate cyclase. The data suggest that the in vitro action of lithium on the adenylate cyclase activity stimulated through the re ceptor, G(s) or the catalytic unit is due to a displacement of Mg2+ fr om the cation site, which modulates the catalytic activity. However, t he lithium-Mg2+ interaction did not seem to be involved in the ex vivo action of lithium. Accordingly, the in vitro and ex vivo effects of l ithium on the cAMP production were exerted by distinct mechanisms. The present work, furthermore, revealed that lithium ex vivo exerts regio n-specific effects in the rat brain. Thus, after chronic lithium treat ment Ca2+-CaM-stimulated adenylate cyclase activity was decreased in t he cerebral cortex and corpus striatum, but increased in the hippocamp us. Similarly, lithium ex vivo decreased isoprenaline- and dopamine-st imulated adenylate cyclase activity in the cerebral cortex and corpus striatum, respectively; but tended to increase 5-HT-stimulated adenyla te cyclase in the hippocampus. The latter actions were dependent on th e concentrations of GTP. This indicates that lithium affects the recep tor-G(s) coupling or the receptor-induced stimulation of G(s). Lithium did not seem to affect the rate of activation of G(s). In hippocampus , lithium ex vivo was found to attenuate 5-HT-induced G(i) inhibition of Ca2+-CaM-stimulated adenylate cyclase activity. This 5-HT-mediated inhibition of adenylate cyclase was demonstrated to be mediated throug h the 5-HT1A receptor subtype.