Chronic haloperidol and clozapine produce different patterns of effects on phosphodiesterase-1B, -4B, and -10A...

Phosphodiesterase-10A (PDE10A), -1B (PDE1B), -4B (PDE4B), and -4A (PDE4A) are important regulators of signal transduction in striatum due to their catalysis of cyclic AMP and cyclic GMP. The typical antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine are thought to regulate cyclic nucleotide signaling in striatum. Since this brain region is essential in mediation of both therapeutic and extrapyramidal side effects, it was of interest to determine whether chronic treatment for 21 days with haloperidol (1 mg/kg) or clozapine (20 mg/kg) affected PDE expression in rat striatum. This was accomplished using SDS-PAGE/immunoblotting and real-time RT-PCR. Both antipsychotic drugs increased PDE10A and did not change PDE4A. By contrast, PDE1B was increased by haloperidol treatment, but not clozapine treatment, while PDE4B was increased by clozapine, but not haloperidol. In all cases, changes in protein expression were accompanied by corresponding changes in mRNA, and only were observed with chronic treatment. Up-regulation of PDEs may represent compensatory responses to haloperidol and clozapine treatments, due to altered cyclic nucleotide signaling, and that different patterns of effects produced by these drugs may be associated with their mechanisms of action.