Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine

Abstract

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is deficient in schizophrenia patients. In rats, PPI deficits induced by dopamine (DA) agonists are reversed by antipsychotics. Inhibition of the striatum-rich phosphodiesterase (PDE)10A may represent a novel antipsychotic mechanism. Previous studies were controversial, showing antipsychotic-like profiles in measures of PPI for the preferential PDE10A inhibitor papaverine (PAP) but not the novel PDE10A inhibitor TP-10. The aim of the study was to evaluate the antipsychotic profile of PAP in rats using PPI. PPI deficits were induced in rats by apomorphine (APO; 0.1, 0.5 mg/kg) or D: -amphetamine (AMPH; 4 mg/kg). PAP (3, 10, 30 mg/kg) or haloperidol (HAL; 0.1 mg/kg) was tested against these agonists in Sprague-Dawley (SD) or Wistar (WI) rats. Prepulse intervals ranged from 10 to 120 ms. Further tests evaluated the effects of PAP on spontaneous locomotion, AMPH (1 mg/kg)-induced hyperlocomotion, and core body temperature (T degrees ). HAL reversed APO-induced PPI deficits but PAP failed to reverse APO- and AMPH-induced PPI deficits at all doses, strains, pretreatment times, and prepulse intervals. PAP (30 mg/kg) significantly reduced AMPH hyperlocomotion in SD rats, and a similar pattern was detected in WI rats. This PAP dose also strongly reduced spontaneous locomotion and T degrees in SD rats. Our study does not support an antipsychotic-like profile of PAP in dopaminergic PPI models.