Blockade of GluA1 AMPA receptors reduces impulsive behavior in a gambling addiction model by modulating extracellular dopamine levels

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Abstract

BACKGROUND: The search for new agents for the pharmacological management of gambling addiction remains an urgent task in contemporary psychoneuropharmacology. A GluA1 AMPA receptor antagonist (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist), IEM-1460, has previously been proposed as a potential therapeutic option for addiction. Glutamatergic inputs are known to modulate the activity of the mesolimbic dopamine system. It can be hypothesized that the antiaddictive effect of IEM-1460 is mediated through the interaction between glutamatergic and dopaminergic systems.

AIM: The work aimed to investigate the effect of GluA1 AMPA receptor blockade on impulsive behavior in a gambling addiction model, its role in modulating extracellular dopamine levels in the nucleus accumbens, and its effects on ion currents in isolated neurons.

METHODS: Experiments were conducted in vivo in Wistar rats and in vitro in isolated Danio rerio neurons. The effect of IEM-1460 (1, 3, and 10 mg/kg, intraperitoneally) on impulsive behavior in a gambling addiction model using a three-arm maze, and on dopamine release in the nucleus accumbens in response to electrical stimulation of the ventral tegmental area, was assessed using intravital fast-scan cyclic voltammetry. In isolated Danio rerio neurons, the effect of IEM-1460 on ion currents induced by the AMPA receptor agonist kainic acid was evaluated using the patch-clamp technique.

RESULTS: IEM-1460 at 1 mg/kg administered intraperitoneally most effectively reduced impulsive behavior in the gambling addiction model and increased dopamine release in the nucleus accumbens in response to electrical stimulation of the ventral tegmental area. In vitro, IEM-1460 produced a pronounced blocking effect on AMPA glutamate receptors.

CONCLUSION: Selective blockade of GluA1-AMPA receptors with IEM-1460 reduced impulsive behavior in the gambling addiction model and increased extracellular dopamine levels in the nucleus accumbens, as measured by fast-scan cyclic voltammetry.

About the authors

Andrei A. Lebedev

Institute of Experimental Medicine; St. Petersburg State Institute of Psychology and Social Work

Email: aalebedev-iem@rambler.ru
ORCID iD: 0000-0003-0297-0425
SPIN-code: 4998-5204

Dr. Sci. (Biology), Professor

Russian Federation, Saint Petersburg; Saint Petersburg

Aleksandr M. Potapkin

Institute of Experimental Medicine; St. Petersburg State Institute of Psychology and Social Work

Author for correspondence.
Email: potanin.alexander@yandex.ru
ORCID iD: 0009-0009-6034-364X

MD, Cand. Sci. (Medicine)

Russian Federation, Saint Petersburg; Saint Petersburg

Sarng S. Pyurveev

Institute of Experimental Medicine

Email: dr.purveev@gmail.com
ORCID iD: 0000-0002-4467-2269
SPIN-code: 5915-9767

MD, Cand. Sci. (Medicine);

Russian Federation, Saint Petersburg

Vadim V. Sizov

Institute of Experimental Medicine

Email: sizoff@list.ru
ORCID iD: 0009-0001-6198-1821
SPIN-code: 1397-7380
Russian Federation, Saint Petersburg

Valerii E. Gmiro

Institute of Experimental Medicine

Email: g2119@online.ru
SPIN-code: 1526-2154

Cand. Sci. (Chemistry)

Russian Federation, Saint Petersburg

Eugenii R. Bychkov

Institute of Experimental Medicine

Email: bychkov@mail.ru
ORCID iD: 0000-0002-8911-6805
SPIN-code: 9408-0799

MD, Dr. Sci. (Medicine)

Russian Federation, Saint Petersburg

Valery N. Mukhin

Institute of Experimental Medicine

Email: Valery.Mukhin@gmail.com
ORCID iD: 0000-0003-0999-6847
SPIN-code: 3655-9126

MD, Cand. Sci. (Medicine)

Russian Federation, Saint Petersburg

Mariia A. Netesa

Institute of Experimental Medicine

Email: aintula@gmail.com
ORCID iD: 0009-0002-7353-1745
SPIN-code: 8429-6486
Russian Federation, Saint Petersburg

Dmitrii E. Anisimov

Institute of Experimental Medicine

Email: anisimov_bb@mail.ru
Russian Federation, Saint Petersburg

Andrey V. Droblenkov

Institute of Experimental Medicine

Email: droblenkov_a@mail.ru
ORCID iD: 0000-0001-5155-1484

Dr. Med. Sci. (Medicine), Professor

Russian Federation, Saint Petersburg

Petr D. Shabanov

Institute of Experimental Medicine

Email: pdshabanov@mail.ru
ORCID iD: 0000-0003-1464-1127
SPIN-code: 8974-7477

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Saint Petersburg

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