Mechanisms of the Pharmacological Modulation of Obsessive-Compulsive and Cognitive Disorders in Cats Recognized by the Method of Normalizing FFT-Convertible Functions of Electrograms of the Frontal Cortex and Hippocampus

The pharmacological modulation and analysis of psychopathological processes in animals is a research method providing a possibility to study similar processes in humans. Methods and approaches based on the principles of the pharmacological modulation of systemic behaviour and normalization of FFT-transformed functions of the brain electrograms allow identification of the quantitative parameters of intracentral relations, cognitive functions and fundamental mechanisms for evaluating the effects of neuropsychoactive drugs in the whole brain in vivo.

The work was carried out on cats with stereotactically implanted electrodes in the brain. Subtherapeutic doses of ketamine, amphetamine and nakom were used to model obsessive-compulsive disorders and cognitive changes. The pharmacological modulation of the animals’ behaviour was evaluated by the effect on the frontal brain and hippocampus. The activation of γ-rhythms (from 35 to 60 Hz) was considered as an improvement in cognitive functions. Ketamine exhibited a more pronounced depressing effect on the proreal gyrus, with its activating effects being close to amphetamine across the frequency ranges of 11–15 and 32–35 Hz. Ketamine had a pronounced activating effect on the gyrus suprasilvium anterior and the hippocampus. Ketamin and nakom demonstrated similar effects in the area of the proreal gyrus, most clearly manifested at frequencies of about 9–15 and 35–36 Hz. The action of nakom was characterized by the episodes of activation in a higher frequency range of 40–55 Hz as well. In the area of the gyrus suprasilvium anterior, the effects of nakom were similar to those of ketamine; however, these substances exhibited different effects in the range of 9–11 Hz. Compared to amphetamine, nakom showed no depressing episodes over the high-frequency range of 55–65 Hz. In the hippocampus, nakom demonstrated an activating effect exceeding that of ketamine by 100–150%. It was shown that neuroimaging of the normalized functions of electrograms during the pharmacological modulation of obsessive-compulsive and cognitive disorders reflects the most striking transformations in high-frequency brain rhythms, primarily related to the γ-range.

Comparison of the results of pharmacomodulation with the pharmacodynamic and pharmacokinetic parameters of drugs when modelling psychopathologies in animals helps researchers in their search for approaches to modifying animal behaviour and extrapolating them to humans.

1. Karkischenko V.N., Karkischenko N.N., Shustov E.B. Farmakologicheskie osnovy terapii. Tezaurus: Ruk-vo dlya vrachej i studentov [Pharmacological basis of therapy. Thesaurus: Manual for doctors and students]. 3rd ed. — new ed. Moscow, Saint Petersburg: Ajsing Publ., 2018. 288 p. (In Russian)

2. Karkischenko N.N. Al’ternativy biomediciny. T. 2. Klassika i al’ternativy farmakotoksikologii [Alternatives to biomedicine. Vol. 2. Classics and alternatives to pharmacotoxicology]. Moscow: VPK Publ., 2007. 448 p. (In Russian)

3. Karkischenko N.N. Psihounitropizm lekarstvennyh sredstv [Psychunitropism of medicines]. Moscow: Medicina Publ., 1993. 208 p. (In Russian)

4. Karkischenko N.N. Farmakologiya sistemnoj deyatel’nosti mozga [Pharmacology of systemic activity of the brain]. Rostov: Rostizdat Publ., 1975. 152 p. (In Russian)

5. Karkischenko N.N., Karkischenko V.N., Fokin Yu.V., Kharitonov S.Yu. Nejrovizualizaciya effektov psihoaktivnyh sredstv posredstvom normalizacii elektrogramm golovnogo mozga [Neuroimaging of the Effects of Psychoactive Substances by Means of Normalization of Brain Electrograms]. Biomedicine. 2019;15(1):12–34. (In Russian) DOI: 10.33647/2074-5982-15-1-12-34.

6. Karkischenko N.N., Fokin Yu.V., Karkischenko V.N., Taboyakova L.A., Mokrousov M.I., Alimkina O.V. Konvergentnaya validaciya intracentral’nyh otnoshenij golovnogo mozga zhivotnyh [Convergent validation of intracentral relationships of the brain of animals]. Biomedicine, 2017;3:16–39. (In Russian)

7. Karkischenko N.N., Fokin Yu.V., Karkischenko V.N., Taboyakova L.A., Kharitonov S.Yu., Alimkina O.V. Novye podhody k ocenke intracentral’nyh otnoshenij po pokazatelyam operantnogo povedeniya i ehlektrogramm mozga koshek [New approaches to the assessment of intracentral relations in terms of operant behavior and electrograms of the cats brain]. Biomedicine, 2018;4:4–17. (In Russian)

8. Rajkroft Ch. Kriticheskij slovar’ psihoanaliza [Critical Dictionary of Psychoanalysis]. Transl. from English by S.V. Voronin, I.N. Gvozdev. Saint Petersburg: Vostochno-Evropejskij institut psihoanaliza Publ., 1995. 250 p. (In Russian)

9. [Rukovodstvo po laboratornym zhivotnym i al’ternativnym modelyam v biomedicinskih issledovaniyah [Manual on laboratory animals and alternative models in biomedical research]. Ed. by N.N. Karkischenko, et al. Moscow: Profil’-2S Publ., 2010. 358 p. (In Russian)

10. Fedorova N.V. Lechenie bolezni Parkinsona [Parkinson’s disease treatment]. Russian Medical Journal. 2001;Special issue:24–33. (In Russian)

11. Fokin Yu.V. Sravnitel’naya ocenka vliyaniya psihoaktivnyh sredstv na gippokampal’nye teta- i gamma-ritmy [Comparative evaluation of the influence of psychoactive medicines on hippocampal teta and gamma rhythms]. Biomeditsina [Journal Biomed]. 2019;15(3):23–32. (In Russian) DOI: 10.33647/2074-5982-15-3-23-32.

12. Tsirkin V.I., Truhina S.I. Fiziologicheskie osnovy psihicheskoj deyatel’nosti i povedeniya cheloveka [The physiological basis of mental activity and human behavior]. Moscow: Med. kniga Publ., 2001. 524 p. (In Russian)

13. Bradshaw J.W.S., Neville P.F., Sawyer D. Factors affecting pica in the domestic cat. Applied Animal Behaviour Science. 1997;52(3–4):373–379. DOI: 10.1016/s0168-1591(96)01136-7.

14. Bragin A., Jandó G., Nádasdy Z., Hetke J., Wise K., Buzsáki G. Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat. J. Neurosci. 1995;15(1, Pt 1):47–60.

15. Brimberg L., Flaisher-Grinberg S., Schilman E.A., Joel D. Strain differences in ‘compulsive’ leverpressing. Behav. Brain Res. 2007;179(1):141–151. DOI: 10.1016/j.bbr.2007.01.014. PMID 17320982.

16. Brüne M. The evolutionary psychology of obsessive-compulsive disorder: the role of cognitive metarepresentation. Perspect Biol. Med. 2006;49(3):317–329. DOI: 10.1353/pbm.2006.0037. PMID 16960303.

17. Citri A., Malenka R. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology. 2008;33(1):18–41.

18. Dvorkin A., Perreault M.L., Szechtman H. Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive-compulsive disorder. Behav. Brain Res. 2006;169(2):303–311. DOI: 10.1016/j.bbr.2006.01.024.

19. Garner J.P., et al. Genetic, environmental and neighbor effects on severity of stereotypies and feather picking in Orange-winged Amazon parrots (Amazona amazonica): An epidemiological study. Applied Animal Behaviour Science. 2006;96: 153–168. DOI: 10.1016/j.applanim.2005.09.009.

20. Graef A. Can dogs lead us to a cure for obsessive-compulsive disorder? Care 2 Make a Difference. 2013.

21. Hyman S., Malenka R., Nestler E. Neural mechanisms of addiction: the role of reward-related learning and memory. Ann. Rev. Neurosci. 2006;29:565–598.

22. Kalueff A.V., Tuohimaa P. Experimental modeli of anxiety and depression. Acta Neurobiol. Exp. 2004;64(4):439–448. PMID 15586660.

23. Kann O. The interneuron energy hypothesis: Implications for brain disease. Neurobiol. Dis. 2016;90:75–85. DOI: 10.1016/j.nbd.2015.08.005.

24. Kann O., Huchzermeyer C., Kovács R., Wirtz S., Schuelke M. Gamma oscillations in the hippocampus require high complex I gene expression and strong functional performance of mitochondria. Brain. 2011;134(Pt 2):345–358. DOI: 10.1093/brain/awq333.

25. Miller J.A. Look who’s clucking! Bioscience. 1992;(42:4):257–259. JSTOR 1311673.

26. Nesse R.M. Is depression an adaptation? Arch Gen Psychiatry. 2000;57(1):14-20. DOI: 10.1001/archpsyc.57.1.14.

27. Nilsson L.-G., Markowitsch H.J. Cognitive Neuroscience of Memory. Seattle: Hogrefe & Huber Publ., 1999. 57 p.

28. Overall K.L., Dunham A.E. Clinical features and outcome in dogs and cats with obsessive-compulsive disorder: 126 cases (1989–2000). J. Am. Vet. Med. Assoc. 2002;221(10):1445–1452. DOI: 10.2460/javma.2002.221.1445.

29. Pharma Business Week. Canine compulsive disorder gene identified in dogs. 2010. 118 p.

30. Polunina A.G., Davydov D.M. EEG correlates of Wechsler Adult Intelligence Scale. Int. J. Neurosc. 2006;116(10):1231–1248.

31. Sershen H., Hashim A., Lajtha A. Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release. Brain Res. 1998;801(1–2):67–71.

32. Shih J., Chen K., Ridd M. Role of MAO A and B in neurotransmitter metabolism and behavior. Pol. J. Pharmacol. 1999;51(1):25–29.

33. Siegel S., Hinson R.E., Krank M.D. The role of predrug signals in morphine analgesic tolerance: support for a Pavlovian conditioning model of tolerance. J. Exp. Psychol. Anim. Behav. Process. 1978;4(2):188–196. DOI: 10.1037/0097-7403.4.2.188.

34. Tort A.B., Kramer M.A., Thorn C., Gibson D.J., Kubota Y., Graybiel A.M., et al. Dynamic crossfrequency couplings of local field potential oscillations in rat striatum and hippocampus during performance of a T-maze task. Proc. Natl Acad. Sci. USA. 2008;105(51):2051720522. DOI: 10.1073/pnas.0810524105.

35. Vermeire S., Audenaert K., De Meester R., Vandermeulen E., Waelbers T., De Spiegeleer B., et al. Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder. Psychiatry Res. 2012;201(1):78–87. DOI: 10.1016/j.pscychresns.2011.06.006.