Vol 13, No 3 (2022)


Selective antagonists of calcium-permeable GluA1 AMPA-receptors as potential antiaddictive agents

Potapkin A.M., Gmiro V.E., Shabanov P.D.


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.

Psychopharmacology & biological narcology. 2022;13(3):7-30
pages 7-30 views


Possible autoimmune mechanisms of regulation of rat behavior in the “open field” test

Baturin V.A., Beyer E.V., Baturina M.V.


BACKGROUND: In recent years, researchers have demonstrated interest in the autoimmune mechanisms of regulation of physiological processes. In response to damage or protein expression, the levels of autoantibodies increased to ensure the restoration of the disturbed balance. Levels of autoantibodies are high in many diseases.

AIM: The aim of this study was to assess the levels of autoantibodies in the blood serum of experimental animals and evaluate their behavior in the “open field” test.

MATERIALS AND METHODS: Of 32 male rats, two groups were formed: group 1 was not exposed to stress, whereas group 2 was subjected to stress for 7 days by applying a clamp on the skin fold for 15 min daily. Three days after the last stress procedure, testing was conducted in the “open field.” After assessing the behavior, blood serum was obtained, and the levels of autoantibodies to dopamine receptors (DR1 and DR2) and NMDA receptors (NR1, NR2A, and NR2B) were determined.

RESULTS: Compared with group 1, group 2 visited the central zones of the field less often, had lower vertical activity, and less often performed acts of washing. In group 2, the levels of autoantibodies to DR1 and DR2 were higher, but to NR2B were lower. Correlation analysis revealed that in group 2, the level of autoantibodies to DR2 was associated with horizontal activity (r = –0.60). In group 1, a relationship was established between the level of autoantibodies to NR2B and the number of runs through the central zones of the field (r = +0.68).

CONCLUSIONS: Taking into account the revealed relationship between the levels of autoantibodies and activity in the open field, the degree of increase in blood IgG titers to DR2 receptors may reflect the severity of changes in the behaviors of animals under stress. Conversely, in connection with the emerging data on the possibility of IgG penetration through the blood–brain barrier, the effect of autoantibodies on brain dopamine receptors with a limited activity of the dopaminergic system may be considered.

Psychopharmacology & biological narcology. 2022;13(3):31-35
pages 31-35 views

Ghrelin levels in different brain regions in Danio rerio exposured to stress

Blazhenko A.A., Khokhlov P.P., Lebedev A.A., Bychkov E.R., Kazakov S.V., Shabanov P.D.


BACKGROUND: Literature data indicated that ghrelin may be a stress neuropeptide in some animals, including Danio rerio.

AIM: The aim of the study was to measure the levels of ghrelin in Danio rerio brain (forebrain, midbrain, and hindbrain) after predator exposure (predator stress test) and administration of ghrelin and oxytocin antagonists to assess the role of ghrelin in stress response.

MATERIALS AND METHODS: The study used 68 Danio rerio, one predator of Cichlasoma nicaraguensis. Ghrelin levels were measured by enzyme-linked immunosorbent assay. The following pharmacological agents were used: 1) ghrelin antagonist hexapeptide [D-Lys3]-GHRP-6 (Tocris, UK); 2) recombinant peptide analog of ghrelin — agrelax — with a molecular weight of 3.5 kDa, developed at the IEM (both compounds in equal dosages of 0.333 mg/L); corticoliberin (Tocris) at a dosage of 0.4 mg/L; and oxytocin (Gedeon Richter, Hungary) at a dosage of 3.8 µL (0.005 IU/µL) per 50 mL of aquarium water (0.019 IU/L).

RESULTS: In the control group, ghrelin level was determined only in the hindbrain, and ghrelin levels in the forebrain and midbrain were <4 pg/mg of total protein. Contact with a predator led to a significant increase in ghrelin levels in the forebrain and midbrain, but not in the hindbrain. Thus, in fish forebrain, ghrelin levels increased to 966 ± 12 pg/mg of protein, which is almost a 250-fold increase in the indicator compared with the level in intact animals. In the presence of agrelax, [D-Lys3]-GHRP-6, and oxytocin, ghrelin levels in the forebrain and midbrain of stressed fish decreased approximately equally to 88 ± 3, 97 ± 1, and 115 ± 1 pg/mg protein, respectively.

CONCLUSION: Thus, stress exposure (contact with a predator) significantly increases ghrelin levels in the forebrain and midbrain but decreases in the hindbrain. Stress-protective peptides (oxytocin, [D-Lys3]-GHRP-6, and agrelax) decreased ghrelin levels in the forebrain and midbrain, and to a lesser extent, in the hindbrain when exposed to stress.

Psychopharmacology & biological narcology. 2022;13(3):37-42
pages 37-42 views


On the history of the study of the nervous trophism mechanisms, disorders, and correction in the Institute of Experimental Medicine (100th anniversary of the S.V. Anichkov Department of Pharmacology)

Zabrodin O.N., Strashnov V.I.


The study of the nervous regulation of trophism and its disorders — neurogenic dystrophy of internal organs, and its prevention was one of the main research directions in the Department of Pharmacology of the Institute of Experimental Medicine of the USSR Academy of Medical Sciences. Since the mid-1950s, research has been conducted under the supervision of the department’s head, Academician of the USSR Academy of Medical Sciences, S.V. Anichkov. He emphasized that the study of nervous trophism and its disorders was a major focus of the research of domestic scientists (I.P. Pavlov, L.A. Orbeli, A.D. Speransky, and G.V. Folbort, e.g.).

This paper aims to review the research on the nervous regulation of trophic processes in internal organs (nervous trophism) and correction of its reflex disorders (neurogenic dystrophy) conducted by the staff of the Department of Pharmacology of the Institute of Experimental Medicine of the USSR Academy of Medical Sciences.

The analysis of scientific publications of the Department of Pharmacology in the Institute of Experimental Medicine (Leningrad – Saint Petersburg) within 1948–2010 was conducted.

The study of neurogenic dystrophy of the stomach wall caused by irritation in experimental animals (rats, guinea pigs, and rabbits) of the reflexogenic zone of the pyloroduodenal region or 3-h electroexpression of immobilized rats receives the most attention. Pharmacological, biochemical, and morphological data on the critical role of the sympathetic nervous system in the development and reversal of dystrophic changes in the gastric mucosa, myocardium, liver, and pancreas are presented. The results of successful clinical trials of pharmacological agents restoring sympathetic regulation of gastric and cardiac trophism in treating patients with peptic ulcer disease and myocardial infarction are presented.

Studies on neurogenic dystrophies of internal organs and search of drugs for their prevention and treatment are actual up to now.

Psychopharmacology & biological narcology. 2022;13(3):43-54
pages 43-54 views

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