Psychopharmacology and Addiction BiologyPsychopharmacology and Addiction BiologyПсихофармакология и биологическая наркология1606-81812070-5670Eco-Vector26706910.17816/phbn267069ReviewsНаучные обзорыReview ArticleSelective antagonists of calcium-permeable GluA1 AMPA-receptors as potential antiaddictive agentsСелективные антагонисты кальций-проницаемых GluA1 AMPA-рецепторов в качестве потенциальных антиаддиктивных средствPotapkinAleksandr M.ПотапкинАлександр Михайлович
Russian Federation

MD, Cand. Sci. (Med.)

канд. мед. наук

potanin.alexander@yandex.ru1526-2154GmiroValerii E.ГмироВалерий Евгеньевич
Russian Federation

MD, Cand. Sci. (Chemistry)

канд. хим. наук

g2119@online.ruhttps://orcid.org/0000-0003-1464-11278974-7477ShabanovPetr D.ШабановПетр Дмитриевич
Russian Federation

Dr. Med. Sci. (Pharmacology), Professor

д-р мед. наук, профессор

pdshabanov@mail.ruInstitute of Experimental MedicineИнститут экспериментальной медицины15032023270320231337302202202323022023Copyright ©; 2023, Potapkin A.M., Gmiro V.E., Shabanov P.D.Copyright ©; 2023, Потапкин А.М., Гмиро В.Е., Шабанов П.Д.2023Potapkin A.M., Gmiro V.E., Shabanov P.D.Потапкин А.М., Гмиро В.Е., Шабанов П.Д.https://creativecommons.org/licenses/by-nc-nd/4.0/https://journals.eco-vector.com/1606-8181/article/view/267069

An increase in synaptic dopamine levels, particularly in the nucleus accumbens sheath, is a critical initial response for encoding a drug’s positive effect and the development of associative learning, which is crucial for finding drugs in response to their rewarding effects.

This study aims to review current data describing the role of AMPA glutamate receptors in the pathological drug search that occurs during the transition from drug use to drug abuse.

Publications reviewed and analyzed the journal publications in international databases (PubMed, Web of Science, Scopus, RSCI) on the mechanisms of interaction between dopamine and AMPA glutamate receptors in drug addiction pathogenesis are reviewed and analyzed.

After repeated exposure to psychostimulant drugs, the dopamine response to narcogen administration becomes sensitized, which is responsible for drugs of abuse over other natural reinforcers. The nucleus accumbens contains convergent inputs of dopamine and glutamate, which modulate the response to psychostimulant drugs. Simultaneously, a constant increase in AMPA-receptors lacking the GluA2 subunit was observed, which leads to an increase in conductivity and initiates a cascade of calcium-dependent signaling. With the development of compulsive drug seeking, the expression of AMPA-receptors in the nucleus accumbens increases.

Based on this hypothesis, it is reasonable to propose drugs for the treatment of drug dependence that counteract the neuroplastic changes in AMPA-receptors caused by repeated drug exposure and leading to addiction. IEM-1460 and IEM-2131, which are two GluA1 AMPA blockers, have been proposed as potential therapeutic agents against addiction and other CNS diseases.

Повышение уровня синаптического дофамина, особенно в оболочке прилежащего ядра, является критическим начальным ответом для кодирования положительного эффекта наркотика и развития ассоциативного обучения, которое имеет решающее значение для поиска наркотиков как ответа на их вознаграждающие эффекты.

Цель — обзор современных данных, описывающих роль глутаматных AMPA-рецепторов в патологическом поиске наркотиков, характерном для перехода от употребления наркотиков к злоупотреблению ими.

Рассмотрены и проанализированы публикации в журналах, входящих в международные базы данных (PubMed, Web of Science, Scopus, RSCI), по вопросам механизмов взаимодействия дофамина и глутаматных AMPA-рецепторов в патогенезе формирования наркотической зависимости.

После многократного воздействия психостимулирующих препаратов дофаминовая реакция на введение наркогена становится сенсибилизированной и лежит в основе предпочтительного внимания к наркотикам, вызывающим злоупотребление, по сравнению с другими естественными подкрепляющими средствами. В прилежащем ядре локализованы конвергентные входы дофамина и глутамата, которые модулируют реакцию на психостимулирующие препараты. При этом отмечено постоянное увеличение AMPA-рецепторов, в которых отсутствует субъединица GluA2, что ведет к увеличению проводимости, а также индуцирует каскад кальций-зависимой передачи сигналов. С развитием компульсивного поиска наркотиков экспрессия рецепторов AMPA в прилежащем ядре увеличивается.

Основываясь на этой гипотезе, для лечения наркотической зависимости целесообразно предложить препараты, противодействующие нейропластическим изменениям в АМРА-рецепторах, вызванным повторным воздействием наркотиков и ведущим к зависимости. В качестве потенциальных лечебных средств против аддикции и других болезней центральной нервной системы предлагаются GluA1 AMPA-блокаторы, в частности, ИЭМ-1460 и ИЭМ-2131.

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