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Pharmacoencephalographic Assessment of Antiphyschotic Agents’ Effect Dose-Dependency in Rats

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Abstract

Pharmacoencephalography (pharmaco-EEG) is a prominent instrument for the pharmacological screening of new psychoactive molecules. This experimental approach has not remained a vestige of neurobiological studies, and can be used successfully to complete today’s research objectives. The development and rise to universal use of machine learning techniques opens up novel prospects for the use of pharmaco-EEG data to solve the problems of classification and prognosis. We have previously shown that naïve Bayes classifier (NBC) combined with principal component analysis (PCA) can be used to differentiate between antipsychotic and sedative drug effects as well as to distinguish among the antipsychotics’ effects. In the present study, we evaluated the possibility to employ this method to assess the dose-dependency of antipsychotic effects. The experiments were carried out in white outbred male rats with chronically implanted electrocorticographic electrodes. As the agents of interest, we chose two drugs with antipsychotic activity, chlorpromazine and promethazine, in three doses each (0.1, 1, 10 mg/kg and 0.5, 5 and 20 mg/kg, respectively). The training set, used as a reference to determine the pharmacological effects of the agents of interest, included the D2-dopamine receptor blocker haloperidol, M-cholinergic receptor blocker tropicamide, H1-histamine receptor blocker chloropyramine, the sedative dexmedetomidine, and the anxiolytic phenazepam. We have shown that the lowest chlorpromazine dose (0.1 mg/kg) can be characterized as antipsychotic with a marked histaminolytic effect, while the highest one (10 mg/kg) exhibits predominantly antipsychotic activity with a cataleptogenic effect. All three doses demonstrated anticholinergic activity, which increased with the dose. For promethazine, we observed a clear dose-dependent shift from antipsychotic action to cataleptogenic, alongside a notable antimuscarinic effect of all doses. None of promethazine doses showed any resemblance to chloropyramine, which probably indicates its anti-dopaminergic and antimuscarinic effects being able to mask its H1-antihistamine effect in the used dose range. In summary, our results demonstrate that NBC combined with PCA can be used to determine the dose-dependency of antipsychotic agents’ effects based on their impact on electrocorticogram parameters. Further development of this method as well as expansion of psychotropic agent electropharmacogram library would allow for more precise prediction of pharmacological activity of the agents of interest.

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REFERENCES

  1. Lanzone J, Ricci L, Tombini M, Boscarino M, Mecarelli O, Pulitano P, Di Lazzaro V, Assenza G (2021) The effect of Perampanel on EEG spectral power and connectivity in patients with focal epilepsy. Clin Neurophysiol 132(9): 2176–2183. https://doi.org/10.1016/j.clinph.2021.05.026

    Article  PubMed  Google Scholar 

  2. Hyun J, Baik MJ, Kang UG (2011) Effects of Psychotropic Drugs on Quantitative EEG among Patients with Schizophrenia-spectrum Disorders. Clin Psychopharmacol Neurosci 9(2): 78–85. https://doi.org/10.9758/cpn.2011.9.2.78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nordin C, Krijzer F (1996) Antidepressant and anxiolytic profiles of E-10-hydroxynortriptyline on electrocorticograms of rats. Neuropsychobiology 34(1): 44–48. https://doi.org/10.1159/000119290

    Article  CAS  PubMed  Google Scholar 

  4. Dimpfel W (2007) Characterization of atypical antipsychotic drugs by a late decrease of striatal alpha1 spectral power in the electropharmacogram of freely moving rats. Br J Pharmacol 152(4): 538–548. https://doi.org/10.1038/sj.bjp.0707427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dimpfel W, Hoffmann JA (2010) Electropharmacograms of rasagiline, its metabolite aminoindan and selegiline in the freely moving rat. Neuropsychobiology 62(4): 213–220. https://doi.org/10.1159/000319947

    Article  CAS  PubMed  Google Scholar 

  6. Sysoev YuI, Shits DD, Puchik MM, Prikhodko VA, Idiyatullin RD, Kotelnikova AA, Okovityi SV (2022) Use of Naïve Bayes Classifier to Assess the Effects of Antipsychotic Agents on Brain Electrical Activity Parameters in Rats. J Evol Biochem Physiol 58(4): 1130–1141. https://doi.org/10.1134/S0022093022040160

    Article  CAS  Google Scholar 

  7. Sysoev YuI, Prikhodko VA, Idiyatullin RD, Chernyakov RT, Karev VE, Okovityi SV (2022) A Method for Chronic Registration of Brain Cortical Electrical Activity in Rats. J Evol Bioch Physiol 58: 292–301. https://doi.org/10.31857/S0869813922020091

    Article  Google Scholar 

  8. Hansen IH, Agerskov C, Arvastson L, Bastlund JF, Sørensen HBD, Herrik KF (2019) Pharmacoelectroencephalographic responses in the rat differ between active and inactive locomotor states. Eur J Neurosci 50(2): 1948–1971. https://doi.org/10.1111/ejn.14373

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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 156(2–3): 117–154. https://doi.org/10.1007/s002130100811

    Article  CAS  PubMed  Google Scholar 

  10. Waku I, Magalhães MS, Alves CO, de Oliveira AR (2021) Haloperidol-induced catalepsy as an animal model for parkinsonism: A systematic review of experimental studies. Eur J Neurosci 53(11): 3743–3767. https://doi.org/10.1111/ejn.15222

    Article  CAS  PubMed  Google Scholar 

  11. Gardner DM, Baldessarini RJ, Waraich P (2005) Modern antipsychotic drugs: a critical overview. CMAJ 172(13): 1703–1711. https://doi.org/10.1503/cmaj.1041064

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bryant SM, Rhee JW, Thompson TM, Lu JJ, Aks SE (2009) Parenteral ophthalmic tropicamide or cyclopentolate protects rats from lethal organophosphate poisoning. Am J Ther 16(3): 231–234. https://doi.org/10.1097/MJT.0b013e318182254b

    Article  PubMed  Google Scholar 

  13. Kamei C, Ohuchi M, Sugimoto Y, Okuma C (2000) Mechanism responsible for epileptogenic activity by first-generation H1-antagonists in rats. Brain Res 887(1): 183–186. https://doi.org/10.1016/s0006-8993(00)03041-9

    Article  CAS  PubMed  Google Scholar 

  14. Hunter JC, Fontana DJ, Hedley LR, Jasper JR, Lewis R, Link RE, Secchi R, Sutton J, Eglen RM (1997) Assessment of the role of alpha2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice. Br J Pharmacol 122(7): 1339–1344. https://doi.org/10.1038/sj.bjp.0701520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arushanyan EB, Beyer EV, Kaminskaya OV, Sotnikova LK (2015) Positive aspects of the combined effect of melatonin and phenazepam on the behavioral activity of rats. Med Herald North Caucasus 1(37): 84–88. https://doi.org/10.14300/mnnc.2015.10014

    Article  Google Scholar 

  16. Kan AV, Prikhodko VA, Sysoev YuI, Okovity SV (2021) Effect of phenazepam on the amplitude characteristics of electrocorticogram rhythms in rats. Bull Med Sci 4(24): 108–111. https://doi.org/10.31684/25418475-2021-4-108

    Article  Google Scholar 

  17. Garrity AG, Botta S, Lazar SB, Swor E, Vanini G, Baghdoyan HA, Lydic R (2015) Dexmedetomidine-induced sedation does not mimic the neurobehavioral phenotypes of sleep in Sprague Dawley rat. Sleep 38(1): 73–84. https://doi.org/10.5665/sleep.4328

    Article  PubMed  PubMed Central  Google Scholar 

  18. Paalzow GHM, Paalzow LK (1985) Promethazine both facilitates and inhibits nociception in rats: Effect of the testing procedure. Psychopharmacology 85: 31–36. https://doi.org/10.1007/BF00427318

    Article  CAS  PubMed  Google Scholar 

  19. Drozdov AL, Demchenko EM, Eyad A, Nerush OP (2011) The influence of psychotropic drugs on the spontaneous behavioral activity of white rats. Visn Dnipropetrov Univer Biol Med 1(2): 47–53. (In Russ).

    Article  Google Scholar 

  20. Shits DD, Puchik MM, Prikhodko VA, Sysoev YuI, Okovityi SV (2022) Effects of promethazine on the amplitude and spectral characteristics of electrocorticograms in rats. Bull Perm Univ Biol 4: 352–356. https://doi.org/10.17072/1994-9952-2022-4-352-356

    Article  Google Scholar 

  21. Krijzer F, Koopman P, Olivier B (1993) Classification of psychotropic drugs based on pharmacoelectrocorticographic studies in vigilance-controlled rats. Neuropsychobiology 28(3): 122–137. https://doi.org/10.1159/000119015

    Article  CAS  PubMed  Google Scholar 

  22. Dimpfel W (2003) Preclinical data base of pharmaco-specific rat EEG fingerprints (tele-stereo-EEG). Eur J Med Res 8(5): 199–207.

    CAS  PubMed  Google Scholar 

  23. Goryachkina MV, Belousova TA (2014) Chloropyramine: clinical aspects of use. RMJ Med Review 22(24): 1785–1789. (In Russ).

    Google Scholar 

  24. Blessing WW, Blessing EM, Mohammed M, Ootsuka Y (2017) Clozapine, chlorpromazine and risperidone dose-dependently reduce emotional hyperthermia, a biological marker of salience. Psychopharmacology (Berl) 234(21): 3259–3269. https://doi.org/10.1007/s00213-017-4710-x

  25. Rebec GV, Gelman J, Alloway KD, Bashore TR (1983) Cataleptogenic potency of the antipsychotic drugs is inversely correlated with neuronal activity in the amygdaloid complex of the rat. Pharmacol Biochem Behav 19(5): 759–763. https://doi.org/10.1016/0091-3057(83)90076-x

    Article  CAS  PubMed  Google Scholar 

  26. Casey JF, Bennett IF, Lindley CJ, Holister LE, Gordon MH, Springer NN (1960) Drug therapy in schizophrenia. A controlled study of the relative effectiveness of chlorpromazine, promazine, phenobarbital, and placebo. AMA Arch Gen Psychiatry 2: 210–220. https://doi.org/10.1001/archpsyc.1960.03590080086012

    Article  CAS  PubMed  Google Scholar 

  27. Ramachandraiah CT, Subramaniam N, Tancer M (2009) The story of antipsychotics: Past and present. Indian J Psychiatry 51(4): 324–326. https://doi.org/10.4103/0019-5545.58304

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yonemura K, Miyanaga K, Machiyama Y (1998) Profiles of the affinity of antipsychotic drugs for neurotransmitter receptors and their clinical implication. Kitakanto Med J 48(2): 87–102. https://doi.org/10.2974/KMJ.48.87

    Article  CAS  Google Scholar 

  29. Promethazine. Ligand Activity Charts. IUPHAR/BPS Guide to Pharmacology. Mode of access: https://www.guidetopharmacology.org (access from May 29, 2023)

  30. Ghoneim OM, Legere JA, Golbraikh A, Tropsha A, Booth RG (2006) Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes. Bioorg Med Chem 14(19): 6640–6658. https://doi.org/10.1016/j.bmc.2006.05.077

    Article  CAS  PubMed  Google Scholar 

  31. Li P, Snyder GL, Vanover KE (2016) Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future. Curr Top Med Chem 16(29): 3385–3403. https://doi.org/10.2174/1568026616666160608084834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Droperidol. Ligand Activity Charts. IUPHAR/BPS Guide to Pharmacology. Mode of access: https://www.guidetopharmacology.org (access from May 29, 2023)

  33. Donahue TJ, Hillhouse TM, Webster KA, Young R, De Oliveira EO, Porter JH (2017) Discriminative stimulus properties of the atypical antipsychotic amisulpride: comparison to its isomers and to other benzamide derivatives, antipsychotic, antidepressant, and antianxiety drugs in C57BL/6 mice. Psychopharmacology (Berl) 234(23–24): 3507–3520. https://doi.org/10.1007/s00213-017-4738-y

  34. Meltzer HY, Bobo WV (2012) Antipsychotic and anticholinergic drugs. In: Gelder M (ed) New Oxford Textbook of Psychiatry 2 ed. Oxford Acad, Oxford.

    Google Scholar 

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Funding

This work was supported by Russian Science Foundation grant 23-75-01051 (creation of a library of electrocorticogram records), State Program GP-47 “Scientific and Technological Development of the Russian Federation” (2019–2030), topic 0113-2019-0006 (Yu.I.S.), under the projects 93022925/94030803 St. Petersburg State University (Yu.I.S.) and no. 075-10-2021-093 (Project NRB-RND-2115, Yu.I.S.) with the financial support of the Ministry of Science and Higher Education of the Russian Federation, as well as at the expense of the state assignment of the N.P. Bechtereva Institute of the Human Brain (development of methods of mathematical analysis, topic state registration number 122041500045-8).

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Authors and Affiliations

  1. St. Petersburg State Chemical and Pharmaceutical University, St. Petersburg, Russia

    Yu. I. Sysoev, D. D. Shits, M. M. Puchik, V. A. Prikhodko, I. A. Titovich, N. O. Selizarova & S. V. Okovityi

  2. Pavlov Institute of Physiology of the Russian Academy of Sciences, St. Petersburg, Russia

    Yu. I. Sysoev

  3. Institute of Translational Biomedicine, Saint Petersburg State University, St. Petersburg, Russia

    Yu. I. Sysoev

  4. Bechtereva Institute of the Human Brain, St. Petersburg, Russia

    Yu. I. Sysoev, I. S. Knyazeva, M. S. Korelov, V. A. Prikhodko & S. V. Okovityi

  5. Sirius University of Science and Technology, Sochi, Russia

    Yu. I. Sysoev

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  1. Yu. I. Sysoev
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Contributions

Idea of work and planning the experiment (Yu.I.S., S.V.O.), experimentation and data processing (Yu.I.S., M.V.S., D.D.Sh., M.M.P., I.S.K., M.S.K.), preparing illustrations (Yu.I.S., V.A.P., I.S.K., M.S.K.), writing and editing the manuscript (Yu.I.S., V.A.P., I.A.T., N.O.S., S.V.O.).

Corresponding author

Correspondence to Yu. I. Sysoev.

Ethics declarations

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Experiments using laboratory animals were performed in accordance with the requirements of Directive 2010/63/EU of the European Parliament and Council of September 22, 2010, the principles of the Basel Declaration and the requirements of the Council of the Eurasian Economic Union from November 03, 2016 no. 81 “On Approval of the Rules of Good Laboratory Practice of the Eurasian Economic Union in the field of circulation of medicines”. The protocol of the experiment was approved by the bioethical commission of Saint Petersburg State Chemical and Pharmaceutical University of the Ministry of Health of Russia (protocol-application R-PEEG2-SA-2022 dated February 15, 2022). All measures were taken to reduce the number of animals used and minimize their suffering.

CONFLICT OF INTEREST

The authors of this work declare that they have no conflicts of interest

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Translated by A. Dyomina

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Russian Text © The Author(s), 2023, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2023, Vol. 109, No. 11, pp. 1665–1683https://doi.org/10.31857/S0869813923110110.

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Sysoev, Y.I., Shits, D.D., Puchik, M.M. et al. Pharmacoencephalographic Assessment of Antiphyschotic Agents’ Effect Dose-Dependency in Rats. J Evol Biochem Phys 59, 2153–2167 (2023). https://doi.org/10.1134/S0022093023060200

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