Skip to main content
SpringerLink
Log in

Behavioral and qEEG effects of the PDE10A inhibitor THPP-1 in a novel rhesus model of antipsychotic activity

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Much preclinical data, almost exclusively using rodent, supports the notion that phosphodiesterase 10A (PDE10A) inhibition may offer an alternative to the current standard of care in schizophrenia. However, concerns persist regarding the clinical translatability of these models for newer drug classes like PDE10A inhibitors.

Objectives

We therefore sought to characterize the clinical standard risperidone and the PDE10A inhibitor THPP-1 in nonhuman primate, both alone and when used as a combination therapy.

Methods

THPP-1 and risperidone were tested in a novel rhesus model of stimulant-induced motor activity (SIMA) and in rhesus electroencephalography (EEG).

Results

Consistent with rodent data, both THPP-1 and risperidone significantly attenuated the stimulant effects in SIMA when administered alone, though some differences were noted. Combination therapy with a low dose of risperidone produced significantly more robust effects. THPP-1 and risperidone also produced a marked reduction of wake cycle time and gamma frequency power in EEG. However, THPP-1 differed from risperidone by reducing spectral power of lower frequencies (delta).

Conclusions

SIMA results suggest that PDE10A inhibition produces antipsychotic-like effects in higher species, and that combination therapy with PDE10A inhibitors may produce more robust efficacy compared to monotherapies. EEG and qEEG results confirm that PDE10A inhibition does share some central signaling effects with clinically effective antipsychotics. The present combination therapy results may carry implications for the manner in which clinical testing of PDE10A inhibitors is conducted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Bleickardt CJ, Kazdoba TM, Jones NT, Hunter JC, Hodgson RA (2014) Antagonism of the adenosine A2A receptor attenuates akathisia-like behavior induced with MP-10 or aripiprazole in a novel non-human primate model. Pharmacol Biochem Behav 118:36–45

    Article  CAS  PubMed  Google Scholar 

  • Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 94:2569–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clemens JA, Smalstig EB, Sawyer BD (1974) Antipsychotic drugs stimulate prolactin release. Psychopharmacologia 40:123–7

    Article  CAS  PubMed  Google Scholar 

  • Cookson JC, Natorf B, Hunt N, Silverstone T, Uppfeldt G (1989) Efficacy, safety and tolerability of raclopride, a specific D2 receptor blocker, in acute schizophrenia: an open trial. Int Clin Psychopharmacol 4:61–70

    Article  CAS  PubMed  Google Scholar 

  • Coskran TM, Morton D, Menniti FS, Adamowicz WO, Kleiman RJ, Ryan AM, Strick CA, Schmidt CJ, Stephenson DT (2006) Immunohistochemical localization of phosphodiesterase 10A in multiple mammalian species. J Histochem Cytochem 54:1205–13

    Article  CAS  PubMed  Google Scholar 

  • Dickerman S, Clark J, Dickerman E, Meites J (1972) Effects of haloperidol on serum and pituitary prolactin and on hypothalamic PIF in rats. Neuroendocrinology 9:332–40

    Article  CAS  PubMed  Google Scholar 

  • Farfel GM, Kleven MS, Woolverton WL, Seiden LS, Perry BD (1992) Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey. Brain Res 578:235–43

    Article  CAS  PubMed  Google Scholar 

  • Gallinat J, Winterer G, Herrmann CS, Senkowski D (2004) Reduced oscillatory gamma-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing. Clin Neurophysiol 115:1863–74

    Article  PubMed  Google Scholar 

  • Gandal MJ, Edgar JC, Klook K, Siegel SJ (2012) Gamma synchrony: towards a translational biomarker for the treatment-resistant symptoms of schizophrenia. Neuropharmacology 62:1504–18

    Article  CAS  PubMed  Google Scholar 

  • Gilmour G, Arguello A, Bari A, Brown VJ, Carter C, Floresco SB, Jentsch DJ, Tait DS, Young JW, Robbins TW (2013) Measuring the construct of executive control in schizophrenia: defining and validating translational animal paradigms for discovery research. Neurosci Biobehav Rev 37:2125–40

    Article  PubMed  Google Scholar 

  • Gloor P (1969) Hans Berger and the discovery of the electroencephalogram. Electroencephalogr Clin Neurophysiol Suppl 28:1–36

    Google Scholar 

  • Gough B, Pereira FC, Fontes Ribeiro CA, Ali SF, Binienda ZK (2014) Propentophylline increases striatal dopamine release but dampens methamphetamine-induced dopamine dynamics: a microdialysis study. Neurochem Int 76:109–13

    Article  CAS  PubMed  Google Scholar 

  • Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R, Langen B, Logue S, Brennan J, Jiang L, Charych E, Egerland U, Liu F, Marquis KL, Malamas M, Hage T, Comery TA, Brandon NJ (2009) Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther 331:574–90

    Article  CAS  PubMed  Google Scholar 

  • Gresack JE, Seymour PA, Schmidt CJ, Risbrough VB (2014) Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating. Psychopharmacology (Berlin) 231:2189–97

    Article  CAS  Google Scholar 

  • Hamon P, Velluz (1952) Effect of R. P. 4560 on maniacal agitation. Ann Med Psychol (Paris) 110:331–5

    CAS  Google Scholar 

  • Harnryd C, Bjerkenstedt L, Gullberg B, Oxenstierna G, Sedvall G, Wiesel FA (1984) Time course for effects of sulpiride and chlorpromazine on monoamine metabolite and prolactin levels in cerebrospinal fluid from schizophrenic patients. Acta Psychiatr Scand Suppl 311:75–92

    Article  CAS  PubMed  Google Scholar 

  • Hiyoshi T, Kambe D, Karasawa J, Chaki S (2014) Involvement of glutamatergic and GABAergic transmission in MK-801-increased gamma band oscillation power in rat cortical electroencephalograms. Neuroscience 280:262–74

    Article  CAS  PubMed  Google Scholar 

  • Hyman SE, Fenton WS (2003) Medicine. What are the right targets for psychopharmacology? Science 299:350–1

    Article  CAS  PubMed  Google Scholar 

  • Jedema HP, Narendran R, Bradberry CW (2014) Amphetamine-induced release of dopamine in primate prefrontal cortex and striatum: striking differences in magnitude and timecourse. J Neurochem 130:490–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones NC, Reddy M, Anderson P, Salzberg MR, O’Brien TJ, Pinault D (2012) Acute administration of typical and atypical antipsychotics reduces EEG gamma power, but only the preclinical compound LY379268 reduces the ketamine-induced rise in gamma power. Int J Neuropsychopharmacol 15:657–68

    Article  CAS  PubMed  Google Scholar 

  • Klett CJ, Caffey E Jr (1972) Evaluating the long-term need for antiparkinson drugs by chronic schizophrenics. Arch Gen Psychiatry 26:374–9

    Article  CAS  PubMed  Google Scholar 

  • Laborit H, Huguenard P, Alluaume R (1952) A new vegetative stabilizer; 4560 R.P. Presse Med 60:206–8

    CAS  PubMed  Google Scholar 

  • Leiser SC, Dunlop J, Bowlby MR, Devilbiss DM (2011) Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research. Biochem Pharmacol 81:1408–21

    Article  CAS  PubMed  Google Scholar 

  • 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 353:1209–23

    Article  CAS  PubMed  Google Scholar 

  • Mabrouk OS, Semaan DZ, Mikelman S, Gnegy ME, Kennedy RT (2014) Amphetamine stimulates movement through thalamocortical glutamate release. J Neurochem 128:152–61

    Article  CAS  PubMed  Google Scholar 

  • Mango D, Bonito-Oliva A, Ledonne A, Nistico R, Castelli V, Giorgi M, Sancesario G, Fisone G, Berretta N, Mercuri NB (2014) Phosphodiesterase 10A controls D1-mediated facilitation of GABA release from striato-nigral projections under normal and dopamine-depleted conditions. Neuropharmacology 76(Pt A):127–36

    Article  CAS  PubMed  Google Scholar 

  • Megens AA, Hendrickx HM, Mahieu MM, Wellens AL, de Boer P, Vanhoof G (2014) PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways. Pharmacol Res Perspect 2:e00057

    Article  PubMed  PubMed Central  Google Scholar 

  • Menniti FS, Chappie TA, Humphrey JM, Schmidt CJ (2007) Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. Curr Opin Investig Drugs 8:54–9

    CAS  PubMed  Google Scholar 

  • Morgan P, Van Der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, Street SD (2012) Can the flow of medicines be improved? fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov Today 17:419–24

    Article  CAS  PubMed  Google Scholar 

  • Mukherjee J, Christian BT, Narayanan TK, Shi B, Mantil J (2001) Evaluation of dopamine D-2 receptor occupancy by clozapine, risperidone, and haloperidol in vivo in the rodent and nonhuman primate brain using 18F-fallypride. Neuropsychopharmacology 25:476–88

    Article  CAS  PubMed  Google Scholar 

  • Muly EC, Votaw JR, Ritchie J, Howell LL (2011) Relationship between dose, drug levels, and D2 receptor occupancy for the atypical antipsychotics risperidone and paliperidone. J Pharmacol Exp Ther 341:81–9

    Article  Google Scholar 

  • Muly EC, Votaw JR, Ritchie J, Howell LL (2012) Relationship between dose, drug levels, and D2 receptor occupancy for the atypical antipsychotics risperidone and paliperidone. J Pharmacol Exp Ther 341:81–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murnane KS, Andersen ML, Rice KC, Howell LL (2013) Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non-human primates. J Sleep Res 22:581–8

    Article  PubMed  Google Scholar 

  • Nishi A, Snyder GL (2010) Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: biochemical and behavioral profiles of phosphodiesterase inhibition in dopaminergic neurotransmission. J Pharmacol Sci 114:6–16

    Article  CAS  PubMed  Google Scholar 

  • Nishi A, Kuroiwa M, Shuto T (2010) Role of phosphodiesterases in dopamine signal transduction. Nihon Yakurigaku Zasshi 135:8–13

    Article  CAS  PubMed  Google Scholar 

  • Piccolino M (1997) Luigi Galvani and animal electricity: two centuries after the foundation of electrophysiology. Trends Neurosci 20:443–8

    Article  CAS  PubMed  Google Scholar 

  • Polissidis A, Chouliara O, Galanopoulos A, Naxakis G, Papahatjis D, Papadopoulou-Daifoti Z, Antoniou K (2014) Cannabinoids negatively modulate striatal glutamate and dopamine release and behavioural output of acute D-amphetamine. Behav Brain Res 270:261–9

    Article  CAS  PubMed  Google Scholar 

  • Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD (2012) Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia. Bioorg Med Chem Lett 22:5903–8

    Article  CAS  PubMed  Google Scholar 

  • Ray WA, Chung CP, Murray KT, Hall K, Stein CM (2009) Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 360:225–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ridley RM, Baker HF, Scraggs PR (1979) The time course of the behavioral effects of amphetamine and their reversal by haloperidol in a primate species. Biol Psychiatry 14:753–65

    CAS  PubMed  Google Scholar 

  • Riedel M, Schwarz MJ, Strassnig M, Spellmann I, Muller-Arends A, Weber K, Zach J, Muller N, Moller HJ (2005) Risperidone plasma levels, clinical response and side-effects. Eur Arch Psychiatry Clin Neurosci 255:261–8

    Article  PubMed  Google Scholar 

  • Sarter M (2004) Animal cognition: defining the issues. Neurosci Biobehav Rev 28:645–50

    Article  PubMed  Google 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 325:681–90

    Article  CAS  PubMed  Google Scholar 

  • Scraggs PR, Ridley RM (1978) Behavioural effects of amphetamine in a small primate: relative potencies of the d- and l-isomers. Psychopharmacology (Berlin) 59:243–5

    Article  CAS  Google Scholar 

  • 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 985:113–26

    Article  CAS  PubMed  Google Scholar 

  • Smith SM, Uslaner JM, Cox CD, Huszar SL, Cannon CE, Vardigan JD, Eddins D, Toolan DM, Kandebo M, Yao L, Raheem IT, Schreier JD, Breslin MJ, Coleman PJ, Renger JJ (2013) The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. Neuropharmacology 64:215–23

    Article  CAS  PubMed  Google Scholar 

  • Sotty F, Montezinho LP, Steiniger-Brach B, Nielsen J (2009) Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to D-amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons. J Neurochem 109:766–75

    Article  CAS  PubMed  Google Scholar 

  • Steriade M, McCormick DA, Sejnowski TJ (1993) Thalamocortical oscillations in the sleeping and aroused brain. Science 262:679–85

    Article  CAS  PubMed  Google Scholar 

  • Symond MP, Harris AW, Gordon E, Williams LM (2005) “Gamma synchrony” in first-episode schizophrenia: a disorder of temporal connectivity? Am J Psychiatry 162:459–65

    Article  PubMed  Google Scholar 

  • Takeuchi H, Suzuki T, Bies RR, Remington G, Mamo DC, Pollock BG, Mimura M, Uchida H (2013) Estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in schizophrenia: an analysis of the CATIE data. Schizophr Res 150:373–9

    Article  PubMed  Google Scholar 

  • Threlfell S, Sammut S, Menniti FS, Schmidt CJ, West AR (2009) Inhibition of phosphodiesterase 10A increases the responsiveness of Striatal projection neurons to cortical stimulation. J Pharmacol Exp Ther 328:785–95

    Article  CAS  PubMed  Google Scholar 

  • Tsutsumi C, Uchida H, Suzuki T, Watanabe K, Takeuchi H, Nakajima S, Kimura Y, Tsutsumi Y, Ishii K, Imasaka Y, Kapur S (2011) The evolution of antipsychotic switch and polypharmacy in natural practice—a longitudinal perspective. Schizophr Res 130:40–6

    Article  PubMed  Google Scholar 

  • Uslaner JM, Tye SJ, Eddins DM, Wang X, Fox SV, Savitz AT, Binns J, Cannon CE, Garson SL, Yao L, Hodgson R, Stevens J, Bowlby MR, Tannenbaum PL, Brunner J, McDonald TP, Gotter AL, Kuduk SD, Coleman PJ, Winrow CJ, Renger JJ (2013) Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Sci Transl Med 5:179ra44

    Article  PubMed  Google Scholar 

  • Uthayathas S, Masilamoni GJ, Shaffer CL, Schmidt CJ, Menniti FS, Papa SM (2014) Phosphodiesterase 10A inhibitor MP-10 effects in primates: comparison with risperidone and mechanistic implications. Neuropharmacology 77:257–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wadenberg ML, Kapur S, Soliman A, Jones C, Vaccarino F (2000) Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats. Psychopharmacology (Berlin) 150:422–9

    Article  CAS  Google Scholar 

  • Wadenberg ML, Soliman A, VanderSpek SC, Kapur S (2001) Dopamine D(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology 25:633–41

    Article  CAS  PubMed  Google Scholar 

  • Wilson C, Terry AV Jr (2010) Neurodevelopmental animal models of schizophrenia: role in novel drug discovery and development. Clin Schizophr Relat Psychoses 4:124–37

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 139:597–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida K, Bies RR, Suzuki T, Remington G, Pollock BG, Mizuno Y, Mimura M, Uchida H (2014) Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data. Schizophr Res 153:184–8

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Merck & Co., Inc., WP45-1114, 770 Sumneytown Pike, West Point, PA, 19486, USA

    Joshua D. Vardigan, Henry S. Lange, Spencer J. Tye, Steven V. Fox, Sean M. Smith & Jason M. Uslaner

Authors
  1. Joshua D. Vardigan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henry S. Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Spencer J. Tye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven V. Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sean M. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jason M. Uslaner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jason M. Uslaner.

Ethics declarations

Conflict of interest

All authors are currently employed at Merck & Co., Inc. or were employed at Merck and Co., Inc. at the time of their contributions.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vardigan, J.D., Lange, H.S., Tye, S.J. et al. Behavioral and qEEG effects of the PDE10A inhibitor THPP-1 in a novel rhesus model of antipsychotic activity. Psychopharmacology 233, 2441–2450 (2016). https://doi.org/10.1007/s00213-016-4290-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4290-1

Keywords

Search

Navigation