uzspbgmuУчёные записки Первого Санкт-Петербургского государственного медицинского университета имени академика И. П. ПавловаThe Scientific Notes of the Pavlov University1607-41812541-8807Academician I.P. Pavlov First St. Petersburg State Medical University10.24884/1607-4181-2023-30-4-32-42uzspbgmu-1014Research ArticleОРИГИНАЛЬНЫЕ РАБОТЫORIGINAL PAPERSТолерантность к парадоксальному увеличению двигательной активности, вызванной ингибированием фосфодиэстеразы 10А, на модели гиподофаминергииTolerance to paradoxical increase in motor activity caused by inhibition of phosphodiesterase 10a in a model of hypodopaminergyhttps://orcid.org/0000-0003-1142-6325ДоротенкоА. Р.DorotenkoA. R.

Доротенко Артем Романович, младший научный сотрудник лаборатории экспериментальной фармакологии аддиктивных состояний отдела психофармакологии Института фармакологии им. А. В. Вальдмана

Санкт-Петербург

Dorotenko Artem R., Junior Research Fellow of the Laboratory of Experimental Pharmacology of Addictive States of the Department of Psychopharmacology of the Institute of Pharmacology named after A.V. Valdman 

Saint Petersburg 

a.r.dorotenko@gmail.comhttps://orcid.org/0000-0001-9251-9923СухановИ. М.SukhanovI. M.

Суханов Илья Михайлович, доктор медицинских наук, зав. лабораторией фармакологии поведения отдела психофармакологии Института фармакологии им. А. В. Вальдмана

Санкт-Петербург

Sukhanov Ilya M., Dr. of Sci. (Med.), Head of the Laboratory of Behavioral Pharmacology of the Department Psychopharmacology of the Institute of Pharmacology named after A.V. Valdman

Saint Petersburg 

ilia.sukhanov@gmail.comhttps://orcid.org/0000-0001-5851-9102СавченкоА. А.SavchenkoA. A.

Савченко Артем Алексеевич, старший лаборант фармакологии поведения отдела психофармакологии Института фармакологии им. А. В. Вальдмана

Санкт-Петербург

Savchenko Artem A., Senior Laboratory Assistant of Behavioral Pharmacology of the Department of Psychopharmacology of the Institute of Pharmacology named after A.V. Valdman

Saint Petersburg 

savcenkoartem334@gmail.comhttps://orcid.org/0000-0001-7100-7857ДраволинаО. А.DravolinaO. A.

Драволина Ольга Андреевна, кандидат биологических наук, зав. лабораторией экспериментальной фармакологии аддиктивных состояний отдела психофармакологии Института фармакологии им. А. В. Вальдмана

Санкт-Петербург

Dravolina Olga A., Cand. of Sci. (Biol.), Head of the Laboratory of Experimental Pharmacology of Addictive States of the Department of Psychopharmacology of the Institute of Pharmacology named after A.V. Valdman

Saint Petersburg 

olga.dravolina@gmail.comhttps://orcid.org/0000-0001-8572-3600БелозерцеваИ. В.BelozertsevaI. V.

Белозерцева Ирина Владимировна, кандидат биологических наук, зав. отделом психофармакологии Института фармакологии им. А. В. Вальдмана

Санкт-Петербург

Belozertseva Irina V., Cand. of Sci. (Biol.), Head of the Department of Psychopharmacology of the Institute of Pharmacology named after A.V. Valdman

Saint Petersburg 

belozertseva@gmail.comФедеральное государственное бюджетное образовательное учреждение высшего образования «Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова» Министерства здравоохранения Российской ФедерацииРоссияPavlov UniversityRussian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования “Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова” Министерства здравоохранения Российской ФедерацииРоссияPavlov UniversityRussian Federation2023081220233043242Copyright © Доротенко А.Р., Суханов И.М., Савченко А.А., Драволина О.А., Белозерцева И.В., 20242024Доротенко А.Р., Суханов И.М., Савченко А.А., Драволина О.А., Белозерцева И.В.Dorotenko A.R., Sukhanov I.M., Savchenko A.A., Dravolina O.A., Belozertseva I.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.sci-notes.ru/jour/article/view/1014Введение

Введение: Фосфодиэстеразы (ФДЭ) – группа ферментов, гидролизующих фосфодиэфирную связь в циклических нуклеотидах. ФДЭ10A в основном представлена в среднеразмерных шипиковых нейронах стриатума. Функционально ингибирование ФДЭ10A имитирует действие агонистов D1-подобных и антагонистов D2-подобных дофаминовых рецепторов, одновременно модулируя «прямой» и «непрямой» стриато-таламо-кортикальные пути мозга. К настоящему моменту охарактеризованы преимущественно эффекты ингибирования ФДЭ10A, воспроизводящие угнетающее двигательную активность действие антагонистов D2-подобных дофаминовых рецепторов.

Цель работы

Цель работы: оценка стимулирующего двигательную активность действия ингибиторов ФДЭ10А, а также возможного развития толерантности к данным эффектам при их повторном введении.

Методы

Методы: Гиподофаминергическое состояние у самцов крыс стока Wistar моделировали введением ингибитора VMAT2 тетрабеназина (3 мг/кг). Эффекты селективных ингибиторов ФДЭ10А, MP-10 (0,3-5 мг/кг) и RO5545965 (0,1-0,9 мг/кг), на двигательную активность крыс оценивали при однократном и повторном введении (5 и 10 дней). 

Результаты

Результаты: Выключение ФДЭ10А дозозависимо стимулировало двигательную активность крыс после введения тетрабеназина. Однако повторное введение ингибиторов ФДЭ10А сопровождалось развитием толерантности к их парадоксальному стимулирующему действию.

Заключение

Заключение: Развитие толерантности может ограничивать потенциальное клиническое использование ингибиторов ФДЭ10А с целью коррекции гиподофаминергических симптомов у пациентов с болезнью Паркинсона. Необходимы исследования молекулярных механизмом данного явления.

Introduction

Introduction. Phosphodiesterases (PDEs) are a group of enzymes that hydrolyze the phosphodiester bond in cyclic nucleotides. PDE10A is mainly present in the medium-sized spiny neurons of the striatum. Functionally, PDE10A inhibition imitates the effect of D1-like agonists and D2-like dopamine receptor antagonists, and simultaneously modulating “direct” and “indirect” striato-thalamo-cortical brain pathway. To date, the effects of PDE10A inhibition have been characterized mainly, reproducing the inhibitory motor activity of D2-like dopamine receptor antagonists.

The objective was to evaluate the stimulating motor activity of the effect of PDE10A inhibitors, as well as the possible development of tolerance to these effects when they are re-administered.

Methods and materials

Methods and materials. The hypodopaminergic state in male Wistar stock rats was modeled by administration of the VMAT2 inhibitor tetrabenazine (3 mg/kg). The effects of selective inhibitors PDE10A, MP-10 (0.3–5 mg/kg) and RO5545965 (0.1–0.9 mg/kg), on the motor activity of rats were evaluated with single and repeated administration (5 and 10 days).

Results

Results. Switching off PDE10A dose-dependently stimulated the motor activity of rats after administration of tetrabenazine. However, repeated administration of PDE10A inhibitors was accompanied by the development of tolerance to their paradoxical stimulating effect.

Conclusion

Conclusion. The development of tolerance may limit the potential clinical use of PDE10A inhibitors to correct hypodopaminergic symptoms in patients with Parkinson’s disease. It is necessary to study the molecular mechanism of this phenomenon.

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The authors declare that there are no conflicts of interest present.