Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine.
BACKGROUND
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.


OBJECTIVE
The aim of the study was to evaluate the antipsychotic profile of PAP in rats using PPI.


METHODS
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 ).


RESULTS
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.


CONCLUSIONS
Our study does not support an antipsychotic-like profile of PAP in dopaminergic PPI models.
Weber
M
M
Department of Psychiatry, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0804, USA.
Breier
M
M
Ko
D
D
Thangaraj
N
N
Marzan
D E
DE
Swerdlow
N R
NR
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D001831:Body Temperature / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010208:Papaverine / Q000493:pharmacokinetics / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects*
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D010726:Phosphodiesterase Inhibitors; D000661:Amphetamine; D010208:Papaverine; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases; D006220:Haloperidol; D001058:Apomorphine