Gi/Go protein-dependent presynaptic mechanisms are involved in clozapine-induced down-regulation of tyrosine hydroxylase in PC12 cells.

Although the clinical effects of antipsychotics have been extensively studied, the molecular mechanisms underlying their antipsychotic activity are unclear. Chronic clozapine has been reported to reduce significantly the expression of tyrosine hydroxylase (TH) in the mesolimbic system. To characterize the mechanisms of action of clozapine on TH expression, PC12 cells turned out to be a useful model, being by far less complex than the entire brain. Both the quantity of TH protein and the amount of TH mRNA in PC12 cells were found to be decreased during incubation of the cells in the presence of clozapine. This decline was followed by a decrease in the enzymatic activity of TH. The effect of clozapine was blocked by preincubation with N-ethylmaleimide, a sulphydryl-alkylating reagent that interferes in Gi/o protein-mediated second messenger pathways. Clozapine may thus decrease TH expression by interacting with Gi/o protein-coupled receptors, such as D2 and 5HT1A. Knowledge of the molecular mechanisms underlying the clinical effects of established antipsychotics will promote the development of new and more efficient antipsychotic drugs.