Actions of lithium on the cyclic AMP signalling system in various regions of the brain--possible relations to its psychotropic actions. A study on the adenylate cyclase in rat cerebral cortex, corpus striatum and hippocampus.

Abstract

It has been estimated that in most industrialized countries 1 person out of every 1000 in the population is undergoing lithium treatment to stabilize their episodic mood disturbances due to manic-depressive illness. Lithium may stabilize mood swings by altering the action of certain neurotransmitters at the synaptic level in the brain. Recent research suggests that lithium alters neurotransmission by affecting neurotransmitter-coupled second messenger systems. A major second messenger system is the adenylate cyclase, which generates intracellular cAMP from ATP. The adenylate cyclases (type I-IV) are regulated by stimulatory and inhibitory receptors, which either stimulate or inhibit the adenylate cyclase activity. The stimulatory and inhibitory neurotransmitter-receptor signals are transferred to the catalytic unit of the adenylate cyclase by Gs and Gi, respectively. The activated receptor induces GTP stimulation of the heterotrimeric G protein, leading to a dissociation of the protein into the active alpha*GTP and the beta gamma complex. The former stimulates the catalytic unit of adenylate cyclase. The stimulation is terminated by a GTPase located on the alpha subunit 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 adenylate cyclases (type I, III) are regulated by CaM as a consequence of enhanced intracellular concentrations of free Ca2+. The Ca(2+)-dependent stimulation of adenylate cyclase by CaM is assumed to occur by a direct effect on the catalytic unit. The catalytic units sensitive to Ca(2+)-CaM are also subjected to regulation by stimulatory and inhibitory neurotransmitter stimuli. Magnesium is essential for adenylate cyclase activity, since MgATP2- is the enzyme substrate. Furthermore, one Mg2+ site located on the G protein regulates both the receptor agonist affinity and the dissociation of the G protein during the activation cycle. A second Mg2+ site on the catalytic unit is responsible for Mg2+ regulation of the catalytic activity. The present work aimed at investigating the mechanisms by which lithium in vitro and after chronic treatment (ex vivo) affects adenylate cyclase activities in various regions of the rat brain. Lithium in vitro and ex vivo inhibited the selective stimulation of adenylate cyclase by Ca(2+)-CaM in the cerebral cortex. Furthermore, lithium in vitro interacted directly with the catalytic unit of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)