Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

Abstract

Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct (dopamine D1 receptor-expressing) and indirect (D2 receptor-expressing striatal output) pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia. To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia. Our results indicate that, in rats: (1) PDE10A inhibition (TP-10, 0.32-10.0mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5mg/kg), confirming previous report; (2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5mg/kg); and attenuated apomorphine-induced disruptions in PPI in the presence of the D1 receptor antagonist SCH23390 (0.005mg/kg). These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. These findings, and the contribution of TP-10 effects in the direct pathway on sensorimotor gating in particular, may have implications for the potential antipsychotic efficacy of PDE10A inhibitors.