, 203:723 | Cite as

Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine

  • M. Weber
  • M. Breier
  • D. Ko
  • N. Thangaraj
  • D. E. Marzan
  • N. R. Swerdlow
Original Investigation



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.


d-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).


  1. 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
  2. Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15:339–343CrossRefPubMedGoogle Scholar
  3. Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156:234–258CrossRefGoogle Scholar
  4. Byrnes EM, Bridges RS, Scanlan VF, Babb JA, Byrnes JJ (2007) Sensorimotor gating and dopamine function in postpartum rats. Neuropsychopharmacology 32:1021–1031CrossRefPubMedGoogle Scholar
  5. 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
  6. 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
  7. Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K (1999) Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem 274:18438–18445CrossRefPubMedGoogle Scholar
  8. Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156:117–154CrossRefGoogle Scholar
  9. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645CrossRefPubMedGoogle Scholar
  10. Graham FK (1975) Presidential address, 1974. The more or less startling effects of weak prestimulation. Psychophysiology 12:238–248CrossRefPubMedGoogle Scholar
  11. Halene TB, Siegel SJ (2007) PDE inhibitors in psychiatry—future options for dementia, depression and schizophrenia. Drug Discov Today 12:870–878CrossRefPubMedGoogle Scholar
  12. 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
  13. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308PubMedGoogle Scholar
  14. Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP (2007) Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity. Neuroscience 144:239–246CrossRefPubMedGoogle Scholar
  15. 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
  16. Kumari V, Das M, Zachariah E, Ettinger U, Sharma T (2005) Reduced prepulse inhibition in unaffected siblings of schizophrenia patients. Psychophysiology 42:588–594CrossRefPubMedGoogle Scholar
  17. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223CrossRefPubMedGoogle Scholar
  18. 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
  19. Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology (Berl) 94:507–514CrossRefGoogle Scholar
  20. Nishi A, Kuroiwa M, Miller DB, O’Callaghan JP, Bateup HS, Shuto T, Sotogaku N, Fukuda T, Heintz N, Greengard P, Snyder GL (2008) Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci 28:10460–10471CrossRefPubMedGoogle Scholar
  21. Randrup A, Munkvad I (1972) Influence of amphetamines on animal behaviour: stereotypy, functional impairment and possible animal–human correlations. Psychiatr Neurol Neurochir 75:193–202PubMedGoogle Scholar
  22. 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
  23. Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, Lanfear J, Ryan AM, Schmidt CJ, Strick CA, Varghese AH, Williams RD, Wylie PG, Menniti FS (2003) Immunohistochemical localization of PDE10A in the rat brain. Brain Res 985:113–126CrossRefPubMedGoogle Scholar
  24. Senogles SE (1994) The D2 dopamine receptor isoforms signal through distinct Gi alpha proteins to inhibit adenylyl cyclase. A study with site-directed mutant Gi alpha proteins. J Biol Chem 269:23120–23127PubMedGoogle Scholar
  25. Shilling PD, Saint Marie RL, Shoemaker JM, Swerdlow NR (2008) Strain differences in the gating-disruptive effects of apomorphine: relationship to gene expression in nucleus accumbens signaling pathways. Biol Psychiatry 63:748–758CrossRefPubMedGoogle Scholar
  26. Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, Shrikhande A, Wong S, Menniti FS, Schmidt CJ (2006) Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 51:386–396CrossRefPubMedGoogle Scholar
  27. Siuciak JA, McCarthy SA, Chapin DS, Martin AN (2008) Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl) 197:115–126CrossRefGoogle Scholar
  28. Swerdlow NR, Braff DL, Taaid N, Geyer MA (1994) Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry 51:139–154PubMedGoogle Scholar
  29. Swerdlow NR, Varty GB, Geyer MA (1998) Discrepant findings of clozapine effects on prepulse inhibition of startle: is it the route or the rat. Neuropsychopharmacology 18:50–56CrossRefPubMedGoogle Scholar
  30. 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
  31. Swerdlow NR, Platten A, Hanlon FM, Martinez ZA, Printz MP, Auerbach P (2003) Sensitivity to sensorimotor gating-disruptive effects of apomorphine in two outbred parental rat strains and their F1 and N2 progeny. Neuropsychopharmacology 28:226–234CrossRefPubMedGoogle Scholar
  32. 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
  33. Swerdlow NR, Shoemaker JM, Bongiovanni MJ, Neary AC, Tochen LS, Saint Marie RL (2005) Reduced startle gating after D1 blockade: effects of concurrent D2 blockade. Pharmacol Biochem Behav 82:293–299CrossRefPubMedGoogle Scholar
  34. Swerdlow NR, Krupin AS, Bongiovanni MJ, Shoemaker JM, Goins JC, Hammer RP Jr (2006) Heritable differences in the dopaminergic regulation of behavior in rats: relationship to D2-like receptor G-protein function. Neuropsychopharmacology 31:721–729CrossRefPubMedGoogle Scholar
  35. Swerdlow NR, Weber M, Qu Y, Light GA, Braff D (2008) Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology 199:331–388CrossRefPubMedGoogle Scholar
  36. Turetsky BI, Calkins ME, Light GA, Olincy A, Radant AD, Swerdlow NR (2007) Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophr Bull 33:69–94CrossRefPubMedGoogle Scholar
  37. Varty GB, Higgins GA (1998) Dopamine agonist-induced hypothermia and disruption of prepulse inhibition: evidence for a role of D3 receptors. Behav Pharmacol 9:445–455CrossRefPubMedGoogle Scholar
  38. Wachtel H (1982) Characteristic behavioural alterations in rats induced by rolipram and other selective adenosine cyclic 3′, 5′-monophosphate phosphodiesterase inhibitors. Psychopharmacology (Berl) 77:309–316CrossRefGoogle Scholar
  39. Xie Z, Adamowicz WO, Eldred WD, Jakowski AB, Kleiman RJ, Morton DG, Stephenson DT, Strick CA, Williams RD, Menniti FS (2006) Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase. Neuroscience 139:597–607CrossRefPubMedGoogle Scholar
  40. Zhang M, Ballard ME, Unger LV, Haupt A, Gross G, Decker MW, Drescher KU, Rueter LE (2007) Effects of antipsychotics and selective D3 antagonists on PPI deficits induced by PD 128907 and apomorphine. Behav Brain Res 182:1–11CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • M. Weber
    • 1
  • M. Breier
    • 1
  • D. Ko
    • 1
  • N. Thangaraj
    • 1
  • D. E. Marzan
    • 1
  • N. R. Swerdlow
    • 1
  1. 1.Department of PsychiatryUCSD School of MedicineLa JollaUSA

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