Studies examining the effect of lithium ions on the synthesis and metabolism of neurotransmitters have, thus far, yielded inconsistent results, failing to shed any light on the mechanism of action of lithium in vivo.
Lithium ions prevent the development of functional supersensitivity to dopamine and acetylcholine receptor stimulation, most likely by influencing second messenger systems.
Lithium ions increase basal cAMP levels and inhibit the neurotransmitter-stimulated accumulation of cAMP in the brain and other tissues.
Acute administration of lithium inhibits the stimulation of adenylyl cyclase, most likely through direct competition with magnesium, whose hydrated ionic radius is similar to that of lithium. The effects of chronic lithium treatment, however, probably result from (a) the modification of gene expression among components of the adenylyl cyclase system, especially G protein subunits (G_i, G_s), as well as from (b) a stabilization of the inactive trimeric form of the Gi protein. Lithium has been found to increase basal cAMP levels, which is most likely due to attenuation of the Gi protein and an increase – probably resulting from the effects of lithium on gene transcription – in the levels of adenylyl cyclase type I and type II mRNA.
At therapeutically relevant concentrations, lithium ions inhibit the hydrolysis of inositol mono-phosphatase to inositol. This leads to a depletion of inositol and a strong increase in diacylglycerol (DAG) in susceptible cells and tissues, depending on species and tissue type. Susceptibility is determined by the activity of a high-affinity inositol transport system, as well as by the degree to which the inositolphospholipid (IP) second messenger system is hormonally stimulated. Pronounced inositol depletion can lead to an inhibition of the IP system in affected cells, which is probably a result of attenuated IP synthesis and/or the activation of protein kinase C (PKC) through the accumulation of DAG.
Lithium exposure facilitates the activation of certain PKC isozymes, chronic activation of which can result in a downregulation of PKC activity (i.e. a constitutive activation and redistribution in the cell nucleus). This process is probably responsible for the diverse effects of lithium on the release of neurotransmitters, the inhibition of receptor sensitization and certain membrane transport processes. By influencing transcription factors such as c-fos, this process could also be responsible for the lithium-induced changes in gene transcription which have been observed.
The inhibitory effects of chronic lithium treatment on the PI system have also been demonstrated in humans. Peripheral cells from manic-depressive patients show increased hormonal sensitivity in the phosphoinositide (PI) system. Thus, it appears that lithium ions might compensate for the hyperactivity of the PI system which is associated with illness in these patients.