Phosphodiesterase 10A as a Therapeutic Target in Neuropsychopharmacology: A Review

INTRODUCTION. Phosphodiesterases (PDEs) are enzymes that regulate intracellular signalling by catalysing the hydrolysis of cyclic nucleotides. The commercial success of selective PDE5 inhibitors for erectile dysfunction and PDE4 inhibitors for respiratory and skin diseases has drawn the close attention of pharmaceutical companies to other PDEs as well. PDE10A, which is expressed in medium spiny neurons (MSNs) of the striatum, deserves special attention as a promising target in psychopharmacology.

AIM. This study aimed to analyse existing preclinical and clinical data on the use of PDE10A inhibitors and to assess possible barriers to the development of medicinal products of this class in neuropsychopharmacology.

DISCUSSION. Preclinical studies have shown that PDE10A inhibitors, which increase the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in MSNs, have antipsychotic and antiparkinsonian properties. Some researchers also believe that PDE10A inhibitors improve cognitive functions. Despite the promising results of preclinical studies, clinical trials of PDE10A inhibitors have not been successful. This review analyses the possible reasons for these failures, including a poor understanding of the function of striatal PDEs in both normal and pathological conditions, the possible development of tolerance to some effects of PDEs, the complex interactions of intracellular cAMP and cGMP signalling pathways, and the intricate workings of the cortico-striato-thalamo-cortical (CSTC) circuits.

CONCLUSIONS. Further research is needed to fully assess the therapeutic potential of PDE10A inhibitors, with a more detailed investigation of the mechanism of action of PDEs, the activity of MSNs, and the CSTC circuits. New data at these three levels of study (subcellular, cellular, and systemic) will create conditions for further development of PDE10A inhibitors.

1. Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 2014;13(4):290–314. https://doi.org/10.1038/nrd4228

2. Komatsu H, Fukuchi M, Habata Y. Potential utility of biased GPCR signaling for treatment of psychiatric disorders. Int J Mol Sci. 2019;20(13):3207. https://doi.org/10.3390/IJMS20133207

3. Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: Essential components in cyclic nucleotide signaling. Annu Rev Biochem. 2007;76:481–511. https://doi.org/10.1146/annurev.biochem.76.060305.150444

4. Omori K, Kotera J. Overview of PDEs and their regulation. Circ Res. 2007;100(3):309–27. https://doi.org/10.1161/01.RES.0000256354.95791.F1

5. Michibata H, Yanaka N, Kanoh Y, Okumura K, Omori K. Human Ca2+/calmodulin-dependent phosphodiesterase PDE1A: Novel splice variants, their specific expression, genomic organization, and chromosomal localization. Biochim Biophys Acta. 2001;1517(2):278–87. https://doi.org/10.1016/S0167-4781(00)00293-1

6. Fidock M, Miller M, Lanfear J. Isolation and differential tissue distribution of two human cDNAs encoding PDE1 splice variants. Cell Signal. 2002;14(1):53–60. https://doi.org/10.1016/S0898-6568(01)00207-8

7. Rosman GJ, Martins TJ, Sonnenburg WK, Beavo JA, Ferguson K, Loughney K. Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3’,5’-cyclic nucleotide phosphodiesterase. Gene. 1997;191(1):89–95. https://doi.org/10.1016/S0378-1119(97)00046-2

8. Degerman E, Belfrage P, Manganiello VC. Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3). J Biol Chem. 1997;272(11):6823–6. https://doi.org/10.1074/JBC.272.11.6823

9. Wallace DA, Johnston LA, Huston E, MacMaster D, Houslay TM, Cheung YF, et al. Identification and characterization of PDE4A11, a novel, widely expressed long isoform encoded by the human PDE4A cAMP phosphodiesterase gene. Mol Pharmacol. 2005;67(6):1920–34. https://doi.org/10.1124/MOL.104.009423

10. Lin CS, Lau A, Tu R, Lue TF. Expression of three isoforms of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in human penile cavernosum. Biochem Biophys Res Commun. 2000;268(2):628–35. https://doi.org/10.1006/BBRC.2000.2187

11. Cote RH. Characteristics of photoreceptor PDE (PDE6): Similarities and differences to PDE5. Int J Impot Res. 2004;16 Suppl 1:S28–33. https://doi.org/10.1038/SJ.IJIR.3901212

12. Glavas NA, Ostenson C, Schaefer JB, Vasta V, Beavo JA. T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3. Proc Natl Acad Sci USA. 2001; 98(11):6319–24. https://doi.org/10.1073/PNAS.101131098

13. Fisher DA, Smith JF, Pillar JS, St. Denis SH, Cheng JB. Isolation and characterization of PDE8A, a novel human cAMP-specific phosphodiesterase. Biochem Biophys Res Commun. 1998;246(3):570–7. https://doi.org/10.1006/BBRC.1998.8684

14. Fisher DA, Smith JF, Pillar JS, St. Denis SH, Cheng JB. Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. J Biol Chem. 1998;273(25):15559–64. https://doi.org/10.1074/JBC.273.25.15559

15. Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi SI, Okumura K, et al. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and GMP (PDE10A). J Biol Chem. 1999;274(26):18438–45. https://doi.org/10.1074/JBC.274.26.18438

16. Yuasa K, Kanoh Y, Okumura K, Omori K. Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. Eur J Biochem. 2001;268(1):168–78. https://doi.org/10.1046/J.1432-1327.2001.01866.X

17. Andersson KE. PDE5 inhibitors — pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol. 2018;175(13):2554–65. https://doi.org/10.1111/BPH.14205

18. Phillips JE. Inhaled phosphodiesterase 4 (PDE4) inhibitors for inflammatory respiratory diseases. Front Pharmacol. 2020;11:259. https://doi.org/10.3389/FPHAR.2020.00259

19. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomised clinical trials. Lancet. 2009;374(9691):685–94. https://doi.org/10.1016/S0140-6736(09)61255-1

20. Crocetti L, Floresta G, Cilibrizzi A, Giovannoni MP. An overview of PDE4 inhibitors in clinical trials: 2010 to early 2022. Molecules. 2022;27(15):4964. https://doi.org/10.3390/MOLECULES27154964

21. Beavo J, Francis S, Houslay M, eds. Cyclic nucleotide phosphodiesterases in health and disease. Boca Raton: CRC Press; 2007. https://doi.org/10.1201/9781420020847

22. Fujishige K, Kotera J, Omori K. Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A. Eur J Biochem. 1999;266(3):1118–27. https://doi.org/10.1046/J.1432-1327.1999.00963.X

23. Kotera J, Fujishige K, Yuasa K, Omori K. Characterization and phosphorylation of PDE10A2, a novel alternative splice variant of human phosphodiesterase that hydrolyzes cAMP and cGMP. Biochem Biophys Res Commun. 1999;261(3):551–7. https://doi.org/10.1006/BBRC.1999.1013

24. Zagorska A, Partyka A, Bucki A, Gawalskax A, Czopek A, Pawlowski M. Phosphodiesterase 10 inhibitors — novel perspectives for psychiatric and neurodegenerative drug discovery. Curr Med Chem. 2018;25(29):3455–81. https://doi.org/10.2174/0929867325666180309110629

25. Macmullen CM, Vick K, Pacifico R, Fallahi-Sichani M, Davis RL. Novel, primate-specific PDE10A isoform highlights gene expression complexity in human striatum with implications on the molecular pathology of bipolar disorder. Transl Psychiatry. 2016;6(2):e742. https://doi.org/10.1038/TP.2016.3

26. MacMullen CM, Fallahi M, Davis RL. Novel PDE10A transcript diversity in the human striatum: Insights into gene complexity, conservation and regulation. Gene. 2017;606:17–24. https://doi.org/10.1016/J.GENE.2016.12.033

27. Jankowska A, Świerczek A, Wyska E, Gawalska A, Bucki A, Pawłowski M, et al. Advances in discovery of PDE10A inhibitors for CNS-related disorders. Part 1: Overview of the chemical and biological research. Curr Drug Targets. 2019;20(1):122–43. https://doi.org/10.2174/1389450119666180808105056

28. Fujishige K, Kotera J, Yuasa K, Omori K. The human phosphodiesterase PDE10A gene genomic organization and evolutionary relatedness with other PDEs containing GAF domains. Eur J Biochem. 2000;267(19):5943–51. https://doi.org/10.1046/J.1432-1327.2000.01661.X

29. Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, et al. Immunohistochemical localization of PDE10A in the rat brain. Brain Res. 2003;985(2):113–26. https://doi.org/10.1016/S0006-8993(03)02754-9

30. Kawaguchi Y. Neostriatal cell subtypes and their functional roles. Neurosci Res. 1997;27(1):1–8. https://doi.org/10.1016/S0168-0102(96)01134-0

31. Nishi A, Kuroiwa M, Miller DB, O’Callaghan JP, Bateup HS, Shuto T, et al. Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci. 2008;28(42):10460–71. https://doi.org/10.1523/JNEUROSCI.2518-08.2008

32. Polli JW, Kincaid RL. Expression of a calmodulin-dependent phosphodiesterase isoform (PDE1B1) correlates with brain regions having extensive dopaminergic innervation. J Neurosci. 1994;14(3 Pt 1):1251–61. https://doi.org/10.1523/JNEUROSCI.14-03-01251.1994

33. Schülke JP, Brandon NJ. Current understanding of PDE10A in the modulation of basal ganglia circuitry. Adv Neurobiol. 2017;17:15–43. https://doi.org/10.1007/978-3-319-58811-7_2

34. Calabresi P, Picconi B, Tozzi A, Ghiglieri V, Di Filippo M. Direct and indirect pathways of basal ganglia: A critical reappraisal. Nat Neurosci. 2014;17(8):1022–30. https://doi.org/10.1038/NN.3743

35. Suzuki K, Harada A, Suzuki H, Miyamoto M, Kimura H. TAK-063, a PDE10A inhibitor with balanced activation of direct and indirect pathways, provides potent antipsychotic-like effects in multiple paradigms. Neuropsychopharmacology. 2016;41(9):2252–62. https://doi.org/10.1038/npp.2016.20

36. Megens AAHP, Hendrickx HMR, Mahieu MMA, Wellens ALY, de Boer P, Vanhoof G. PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways. Pharmacol Res Perspect. 2014;2(4):e00057. https://doi.org/10.1002/PRP2.57

37. Niccolini F, Haider S, Reis Marques T, Muhlert N, Tziortzi AC, Searle GE, et al. Altered PDE10A expression detectable early before symptomatic onset in Huntington’s disease. Brain. 2015;138(Pt 10):3016–29. https://doi.org/10.1093/BRAIN/AWV214

38. Höfgen N, Stange H, Schindler R, Lankau HJ, Grunwald C, Langen B, et al. Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors. J Med Chem. 2010;53(11):4399–411. https://doi.org/10.1021/JM1002793

39. Chappie TA, Helal CJ, Hou X. Current landscape of phosphodiesterase 10A (PDE10A) inhibition. J Med Chem. 2012;55(17):7299–331. https://doi.org/10.1021/JM3004976

40. Bauer U, Giordanetto F, Bauer M, O’Mahony G, Johansson KE, Knecht W, et al. Discovery of 4-hydroxy-1,6-naphthyridine-3-carbonitrile derivatives as novel PDE10A inhibitors. Bioorg Med Chem Lett. 2012;22(5):1944–8. https://doi.org/10.1016/J.BMCL.2012.01.046

41. Das S, Harde RL, Shelke DE, Khairatkar-Joshi N, Bajpai M, Sapalya RS, et al. Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part I. Bioorg Med Chem Lett. 2014;24(9):2073–8. https://doi.org/10.1016/J.BMCL.2014.03.054

42. Kunitomo J, Yoshikawa M, Fushimi M, Kawada A, Quinn JF, Oki H, et al. Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor. J Med Chem. 2014;57(22):9627–43. https://doi.org/10.1021/JM5013648

43. Suzuki K, Harada A, Shiraishi E, Kimura H. In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents. J Pharmacol Exp Ther. 2015;352(3):471–9. https://doi.org/10.1124/JPET.114.218552

44. Hu E, Chen N, Bourbeau MP, Harrington PE, Biswas K, Kunz RK, et al. Discovery of clinical candidate 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a potent, selective, and efficacious inhibitor of phosphodiesterase 10A (PDE10A). J Med Chem. 2014;57(15):6632–41. https://doi.org/10.1021/JM500713J

45. Kehler J, Ritzen A, Langgård M, Petersen SL, Farah MM, Bundgaard C, et al. Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors. Bioorg Med Chem Lett. 2011;21(12):3738–42. https://doi.org/10.1016/J.BMCL.2011.04.067

46. Wagner S, Scheunemann M, Dipper K, Egerland U, Hoefgen N, Steinbach J, et al. Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted imidazo[1,5-a]quinoxalines. Eur J Med Chem. 2016;107:97–108. https://doi.org/10.1016/J.EJMECH.2015.10.028

47. Arakawa K, Maehara S, Yuge N, Ishikawa M, Miyazaki Y, Naba H, et al. Pharmacological characterization of a novel potent, selective, and orally active phosphodiesterase 10A inhibitor, PDM-042 [(E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine] in rats: Potential for the treatment of schizophrenia. Pharmacol Res Perspect. 2016;4(4):e00241. https://doi.org/10.1002/PRP2.241

48. Masilamoni GJ, Uthayathas S, Koenig G, Leventhal L, Papa SM. Effects of a novel phosphodiesterase 10A inhibitor in non-human primates: A therapeutic approach for schizophrenia with improved side effect profile. Neuropharmacology. 2016;110(Pt A):449–57. https://doi.org/10.1016/J.NEUROPHARM.2016.08.012

49. Raheem IT, Schreier JD, Fuerst J, Gantert L, Hostetler ED, Huszar S, et al. Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia. Bioorg Med Chem Lett. 2016;26(1):126–32. https://doi.org/10.1016/J.BMCL.2015.11.013

50. Li YW, Seager MA, Wojcik T, Heman K, Molski TF, Fernandes A, et al. Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy. Neuropharmacology. 2016;102:121–35. https://doi.org/10. 1016/J.NEUROPHARM.2015.10.037

51. Jones PG, Hewitt MC, Campbell JE, Quinton MS, Engel S, Lew R, et al. Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition. Pharmacol Biochem Behav. 2015; 135:46–52. https://doi.org/10.1016/J.PBB.2015.04.017

52. Burdi DF, Campbell JE, Wang J, Zhao S, Zhong H, Wei J, et al. Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A. Bioorg Med Chem Lett. 2015;25(9):1864–8. https://doi.org/10.1016/J.BMCL.2015.03.050

53. Hamaguchi W, Masuda N, Miyamoto S, Kikuchi S, Naraza­ki F, Shiina Y, et al. Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436. Bioorg Med Chem. 2015;23(13):3351–67. https://doi.org/10.1016/J.BMC.2015.04.052

54. Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, et al. Discovery of MK-8189, a highly potent and selective PDE10A inhibitor for the treatment of schizophrenia. J Med Chem. 2023;66(2):1157–71. https://doi.org/10.1021/ACS.JMEDCHEM.2C01521

55. Matloka M, Janowska S, Pankiewicz P, Kokhanovska S, Kos T, Hołuj M, et al. A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects. Front Pharmacol. 2022;13:999685.https://doi.org/10.3389/FPHAR.2022.999685

56. Camacho Gomez J, Castro Palomino Laria J. Pyrimidine derivatives as phosphodiesterase 10 inhibitors (PDE-10). Patent No. US9447095B2.

57. Koizumi Y, Tanaka Y, Matsumura T, Kadoh Y, Miyoshi H, Hongu M, et al. Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety. Bioorg Med Chem. 2019;27(15):3440–50. https://doi.org/10.1016/J.BMC.2019.06.021

58. Takakuwa M, Watanabe Y, Tanaka K, Ishii T, Kagaya K, Tani­guchi H, et al. Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor T-251 in rodents. Pharmacol Biochem Behav. 2019;185:172757. https://doi.org/10.1016/J.PBB.2019.172757

59. Harada A, Kaushal N, Suzuki K, Nakatani A, Bobkov K, Vekich JA, et al. Balanced activation of striatal output pathways by faster off-rate PDE10A inhibitors elicits not only antipsychotic-like effects but also procognitive effects in rodents. Int J Neuropsychopharmacol. 2020;23(2):96–107. https://doi.org/10.1093/IJNP/PYZ056

60. Langen B, Dost R, Egerland U, Stange H, Hoefgen N. Effect of PDE10A inhibitors on MK-801-induced immobility in the forced swim test. Psychopharmacology (Berl). 2012;221(2):249–59. https://doi.org/10.1007/S00213-011-2567-Y

61. Devadiga SJ, Bharate SS. Recent developments in the management of Huntington’s disease. Bioorg Chem. 2022;120:105642. https://doi.org/10.1016/J.BIOORG.2022.105642

62. Suzuki K, Harada A, Suzuki H, Capuani C, Ugolini A, Corsi M, et al. Combined treatment with a selective PDE10A inhibitor TAK-063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic-like effects without affecting plasma prolactin levels and cataleptic responses in rodents. Pharmacol Res Perspect. 2018;6(1):e00372. https://doi.org/10.1002/PRP2.372

63. Megens AAHP, Hendrickx HMR, Hens KA, Fonteyn I, Langlois X, Lenaerts I, et al. Pharmacology of JNJ-42314415, a centrally active phosphodiesterase 10A (PDE10A) inhibitor: A comparison of PDE10A inhibitors with D2 receptor blockers as potential antipsychotic drugs. J Pharmacol Exp Ther. 2014;349(1):138–54. https://doi.org/10.1124/JPET.113.211904

64. Sharma N, Dhiman N, Golani LK, Sharma B. Papaverine ameliorates prenatal alcohol-induced experimental attention deficit hyperactivity disorder by regulating neuronal function, inflammation, and oxidative stress. Int J Dev Neurosci. 2021;81(1):71–81. https://doi.org/10.1002/JDN.10076

65. Luhach K, Kulkarni GT, Singh VP, Sharma B. Attenuation of neurobehavioural abnormalities by papaverine in prenatal val­proic acid rat model of ASD. Eur J Pharmacol. 2021;890:173663. https://doi.org/10.1016/J.EJPHAR.2020.173663

66. Takakuwa M, Watanabe Y, Saijo T, Murata M, Anabuki J, Tezuka T, et al. Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor MT-3014 in rats. Pharmacol Biochem Behav. 2020;196:172972. https://doi.org/10.1016/J.PBB.2020.172972

67. Smith S, Toolan D, Kandebo M, Vardigan J, Raheem I, Layton ME, et al. Preclinical evaluation of MK-8189: A novel phosphodiesterase 10A inhibitor for the treatment of schizophrenia. J Pharmacol Exp Ther. 2025;392(1):100047. https://doi.org/10.1124/JPET.124.002347

68. Shiraishi E, Suzuki K, Harada A, Suzuki N, Kimura H. The phosphodiesterase 10A selective inhibitor TAK-063 improves cognitive functions associated with schizophrenia in rodent models. J Pharmacol Exp Ther. 2016;356(3):587–95. https://doi.org/10.1124/JPET.115.230482

69. Tomimatsu Y, Cash D, Suzuki M, Suzuki K, Bernanos M, Simmons C, et al. TAK-063, a phosphodiesterase 10A inhibitor, modulates neuronal activity in various brain regions in phMRI and EEG studies with and without ketamine challenge. Neuroscience. 2016;339:180–90. https://doi.org/10.1016/J.NEUROSCIENCE.2016.10.006

70. Das S, Shelke DE, Harde RL, Avhad VB, Khairatkar-Joshi N, Gullapalli S, et al. Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part II. Bioorg Med Chem Lett 2014;24:3238–42. https://doi.org/10.1016/J.BMCL.2014.06.028

71. Chen L, Chen D, Tang L, Ren J, Chen J, Zhen X, et al. Design and optimization of purine derivatives as in vivo active PDE10A inhibitors. Bioorg Med Chem. 2017;25(13):3315–29. https://doi.org/10.1016/J.BMC.2017.04.019

72. Harada A, Suzuki K, Kimura H. TAK-063, a novel phosphodiesterase 10A inhibitor, protects from striatal neurodegeneration and ameliorates behavioral deficits in the R6/2 mouse model of Huntington’s disease. J Pharmacol Exp Ther. 2017;360(1):75–83. https://doi.org/10.1124/JPET.116.237388

73. Smith SM, Uslaner JM, Cox CD, Huszar SL, Cannon CE, Vardigan JD, et al. The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. Neuropharmacology. 2013;64:215–23. https://doi.org/10.1016/j.neuropharm.2012.06.013

74. Vardigan JD, Lange HS, Tye SJ, Fox S V., Smith SM, Uslaner JM. Behavioral and qEEG effects of the PDE10A inhibitor THPP-1 in a novel rhesus model of antipsychotic activity. Psychopharmacology (Berl). 2016;233(13):2441–50. https://doi.org/10.1007/S00213-016-4290-1

75. Sukhanov I, Dorotenko A, Fesenko Z, Savchenko A, Efimo­va EV, Mor MS, et al. Inhibition of PDE10A in a new rat model of severe dopamine depletion suggests new approach to non-dopamine Parkinson’s disease therapy. Biomolecules. 2023;13(1):9. https://doi.org/10.3390/BIOM13010009

76. Dorotenko AR, Sukhanov IM, Savchenko AA, Dravolina OA, Belozertseva IV. Tolerance to paradoxical increase in motor activity caused by inhibition of phosphodiesterase 10a in a model of hypodopaminergy. Scientific Notes of the Pavlov University. 2023;30(4):32–42 (In Russ.). https://doi.org/10.24884/1607-4181-2023-30-4-32-42

77. Beck G, Maehara S, Chang PL, Papa SM. A selective phosphodiesterase 10a inhibitor reduces L-dopa-induced dyskinesias in Parkinsonian monkeys. Mov Disord. 2018;33(5):805–14. https://doi.org/10.1002/MDS.27341

78. Bleickardt CJ, Kazdoba TM, Jones NT, Hunter JC, Hodgson RA. 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. 2014;118:36–45. https://doi.org/10.1016/J.PBB.2013.10.030

79. Giampà C, Laurenti D, Anzilotti S, Bernardi G, Menniti FS, Fusco FR. Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington’s disease. PLoS One. 2010;5(10):e13417. https://doi.org/10.1371/JOURNAL.PONE.0013417

80. Kim DY, Park JS, Leem YH, Park JE, Kim HS. The potent PDE10A inhibitor MP-10 (PF-2545920) suppresses microglial activation in LPS-induced neuroinflammation and MPTP-induced Parkinson’s disease mouse models. J Neuroimmune Pharmacol. 2021;16(2):470–82. https://doi.org/10.1007/S11481-020-09943-6

81. Arakawa K, Maehara S. Combination of the phosphodiesterase 10A inhibitor, MR1916 with risperidone shows additive antipsychotic-like effects without affecting cognitive enhancement and cataleptic effects in rats. Neuropsychopharmacol Rep. 2020;40(2):190–5. https://doi.org/10.1002/NPR2.12108

82. Arakawa K, Nakao K, Maehara S. Dopamine D1 signaling involvement in the effects of the phosphodiesterase 10A inhibitor, PDM-042 on cognitive function and extrapyramidal side effect in rats. Behavioural Brain Research. 2017;317:204–9. https://doi.org/10.1016/J.BBR.2016.09.043

83. Redrobe JP, Rasmussen LK, Christoffersen CT, Bundgaard C, Jørgensen M. Characterisation of Lu AF33241: A novel, brain-penetrant, dual inhibitor of phosphodiesterase (PDE) 2A and PDE10A. Eur J Pharmacol. 2015;761:79–85. https://doi.org/10.1016/J.EJPHAR.2015.04.040

84. Gentzel RC, Toolan D, Roberts R, Koser AJ, Kandebo M, Hershey J, et al. The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents. Neuropharmacology. 2015;99:256–63. https://doi.org/10.1016/J.NEUROPHARM.2015.05.024

85. Logrip ML, Vendruscolo LF, Schlosburg JE, Koob GF, Zorrilla EP. Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats. Neuropsychopharmacology. 2014;39(7):1722–31. https://doi.org/10.1038/NPP.2014.20

86. Reneerkens OAH, Rutten K, Bollen E, Hage T, Blokland A, Steinbusch HWM, et al. Inhibition of phoshodiesterase type 2 or type 10 reverses object memory deficits induced by scopolamine or MK-801. Behav Brain Res. 2013;236(1):16–22. https://doi.org/10.1016/J.BBR.2012.08.019

87. Nikiforuk A, Potasiewicz A, Rafa D, Drescher K, Bespalov A, Popik P. The effects of PDE10 inhibition on attentional set-shifting do not depend on the activation of dopamine D1 receptors. Behav Pharmacol. 2016;27(4):331–8. https://doi.org/10.1097/FBP.0000000000000201

88. Wilson L, Brandon N. Emerging biology of PDE10A. Curr Pharm Des. 2015;21(3):378–88. https://doi.org/10.2174/1381612820666140826114744

89. Geerts H, Spiros A, Roberts P. Phosphodiesterase 10 inhibitors in clinical development for CNS disorders. Expert Rev Neurother. 2017;17(6):553–60. https://doi.org/10.1080/14737175.2017.1268531

90. Walling DP, Banerjee A, Dawra V, Boyer S, Schmidt CJ, Demartinis N. Phosphodiesterase 10A inhibitor monotherapy is not an effective treatment of acute schizophrenia. J Clin Psychopharmacol. 2019;39(6):575–82. https://doi.org/10.1097/JCP.0000000000001128

91. Demartinis N, Lopez RN, Pickering EH, Schmidt CJ, Gertsik L, Walling DP, et al. A proof-of-concept study evaluating the phosphodiesterase 10A inhibitor PF-02545920 in the adjunctive treatment of suboptimally controlled symptoms of schizophrenia. J Clin Psychopharmacol. 2019;39(4):318–28. https://doi.org/10.1097/JCP.0000000000001047

92. Macek TA, McCue M, Dong X, Hanson E, Goldsmith P, Affini­to J, et al. A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia. Schizophr Res. 2019;204:289–94. https://doi.org/10.1016/J.SCHRES.2018.08.028

93. Mukai Y, Lupinacci R, Marder S, Snow-Adami L, Voss T, Smith SM, et al. Effects of PDE10A inhibitor MK-8189 in people with an acute episode of schizophrenia: A randomized proof-of-concept clinical trial. Schizophr Res. 2024;270:37–43. https://doi.org/10.1016/J.SCHRES.2024.05.019

94. Delnomdedieu M, Tan Y, Ogden A, Berger Z, Reilmann R. A randomized, double-blind, placebo-controlled phase II efficacy and safety study of the PDE10A inhibitor PF-02545920 in Huntington disease (AMARYLLIS). J Neurol Neurosurg Psychiatry. 2018;89:A99–100. https://doi.org/10.1136/JNNP-2018-EHDN.266

95. Hufgard JR, Williams MT, Skelton MR, Grubisha O, Ferreira FM, Sanger H, et al. Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of PDE10A. Psychopharmacology (Berl). 2017;234(12):1803–13. https://doi.org/10.1007/S00213-017-4587-8