The mechanism(s) of action of treatments known to be antimanic and to stabilize mood in manic-depressive patients are still unknown despite several recently. We have continued working to characterize four antimanic treatments: valproic acid (VPA), carbamazepine (CBZ), lithium, and electroconvulsive shock (ECS)--in terms of their effects on key signal transduction elements including G proteins, adenylate cyclases, isozymes of Protein Kinase C (PKC), transcription factors, and steroid hormones. In C6 cells, chronic VPA increased phosphorylation, but decreased levels of the PKC substrate MARCKS (myristoylated alanine-rich C kinase substrate), consistent with the hypothesis that VPA indirectly activates PKC. In the same system, VPA was found to increase binding of the transcription factor, Activator Protein-1, to DNA within 2 hours, suggesting that a primary target of VPA might produce long-term changes via regulation at the transcriptional level. Finally, in human SK-N-SH neuroblastoma cells, chronic VPA was found to induce increases in PKC a and bII, accompanied by profound morphological changes. Studies with CBZ have identified three potential molecular sites of action: adenylyl cyclase, peripheral benzodiazepine (BDZ) receptors, and 3a-hydroxysteroid oxidoreductase. CNZ directly inhibited adenylyl cyclase purified from a rat brain. In C6 cells, CBZ, acting through peripheral BDZ receptors, increased levels of pregnenolone, a neuroactive steroid precursor. Also in C6 cells, CBZ stimulated 3a-hydroxysteroid oxidoreductase to increase the conversion of progesterone to 3a, 5a- tetrahydroprogesterone (a potent endogenous agonist of the GABAA chloride channel). We have now shown using in vivo microdialysis that chronic lithium affects the intracellular cross-talk between PKC and cAMP induced increased in dialysate cAMP levels in both prefrontal cortex and hippocampus. The post lithium reduced cAMP response to phorbol esters is accompanied by an isozyme-specific decrease in membrane-associated PKC alpha, and to a lesser extent PKC epsilon. Given the critical role of PKC isozymes in 3modulating the cross-talk between neurotransmitter systems and thereby the integrative functions of the CNS, these effects may play a major role in lithium's mood-stabilizing effects.
