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

Abstract

An increase in synaptic dopamine levels, particularly in the nucleus accumbens sheath, is a critical initial response for encoding a drugs 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.