Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine
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.
Materials and 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°).
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° in SD rats.
Our study does not support an antipsychotic-like profile of PAP in dopaminergic PPI models.
Keywordsd-Amphetamine Apomorphine Core body temperature Dopamine Locomotion Papaverine PDE10A Prepulse inhibition
The authors gratefully acknowledge the assistance of Ms. Maria Bongiovanni in manuscript preparation. Research was supported by MH68366. MW was supported by grants from the Tourette Syndrome Association and the National Alliance for Research on Schizophrenia and Depression. NRS has received support from Pfizer Pharmaceuticals (research funding), Allergan Pharmaceuticals (research funding, consultancy), and Sanofi-Aventis (consultancy).
- Bleickardt CJ, Lu SX, Cohen-Williams M, Varty GB, Hodgson RA (2007) Effects of pde10A inhibition with papaverine in rat models of schizophrenia. Society for NeuroscienceGoogle Scholar
- Cadenhead KS, Swerdlow NR, Shafer KM, Diaz M, Braff DL (2000) Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits. Am J Psychiatry 157:1660–1668CrossRefPubMedGoogle Scholar
- Culm KE, Lugo-Escobar N, Hope BT, Hammer RP Jr (2004) Repeated quinpirole treatment increases cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens and reverses quinpirole-induced sensorimotor gating deficits in rats. Neuropsychopharmacology 29:1823–1830CrossRefPubMedGoogle Scholar
- Halene TB, Siegel SJ (2008) Antipsychotic-like properties of phosphodiesterase 4 inhibitors: evaluation of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724) with auditory event-related potentials and prepulse inhibition of startle. J Pharmacol Exp Ther 326:230–239CrossRefPubMedGoogle Scholar
- Kelly MP, Isiegas C, Cheung YF, Tokarczyk J, Yang X, Esposito MF, Rapoport DA, Fabian SA, Siegel SJ, Wand G, Houslay MD, Kanes SJ, Abel T (2007) Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. Neuropsychopharmacology 32:577–588CrossRefPubMedGoogle Scholar
- Lu SX, del Vechhio RA, Kazdoba TM, Leach PT, Werner BJ, Hyde LA, Varty GB, Hodgson RA (2007) Characterization of the PDE10A inhibitor, papaverine, in mouse models of schizophrenia. Society for NeuroscienceGoogle Scholar
- Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, Hoffman WE, Lebel LA, McCarthy SA, Nelson FR, Proulx-LaFrance C, Majchrzak MJ, Ramirez AD, Schmidt K, Seymour PA, Siuciak JA, Tingley FD 3rd, Williams RD, Verhoest PR, Menniti FS (2008) Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther 325:681–690CrossRefPubMedGoogle Scholar
- Swerdlow NR, Martinez ZA, Hanlon FM, Platten A, Farid M, Auerbach P, Braff DL, Geyer MA (2000) Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists. J Neurosci 20:4325–4336PubMedGoogle Scholar
- Swerdlow NR, Shoemaker JM, Auerbach PP, Pitcher L, Goins J, Platten A (2004) Heritable differences in the dopaminergic regulation of sensorimotor gating. II. Temporal, pharmacologic and generational analyses of apomorphine effects on prepulse inhibition. Psychopharmacology (Berl) 174:452–462CrossRefGoogle Scholar