The NR2B subtype of NMDA receptor: a potential target for the treatment of alcohol dependence.
Ethanol is a small molecule acting on several neurotransmitter systems in the brain. Accumulating evidences suggest that the primary excitatory--i.e. the glutamatergic--neurotransmitter system is a particularly important site of ethanol's action. Several studies showed that ethanol is a potent and selective inhibitor of the N-methyl-D-aspartate (NMDA) receptors and prolonged ethanol exposition leads to a compensatory "up-regulation" of these receptors resulting in enhanced NMDA receptor-mediated functions after removal of ethanol. These alterations are supposed to contribute to the development of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal. In recent papers, alterations in subunit composition of NMDA receptors were reported after long term ethanol exposure. mRNA and/or protein levels of NR2A and NR2B types of subunits were found elevated both by in vivo and in vitro experiments. Our results showed that especially the NR2B subunit expression is increased in cultured hippocampal and cortical neurones after 3 days of intermittent ethanol treatment. According to the high calcium permeability, the increased agonist sensitivity and the relatively slow closing kinetics of NMDA ion channels composed of NR2B subunits, the above mentioned changes may underlie the enhanced NMDA receptor activation observed after long term ethanol exposure. Accordingly, we have tested NR2B subunit selective NMDA receptor antagonists in primary cultures of rat cortical neurones pre-treated with ethanol intermittently for 3 days and found that these compounds potently inhibited the neurotoxic effect of ethanol withdrawal. Hypothesising the involvement of enhanced NR2B subunit expression in development of alcohol dependence and withdrawal symptoms and considering the tolerable side effect profile of the NR2B subunit selective NMDA receptor antagonists, the NR2B type of NMDA receptor subunit may serve as a possible drug target in pharmacological interventions for alcoholism. The aim of this review is to give an update on the role of altered structure and function of NMDA receptors after ethanol exposure and to summarise the recent data about the activity of NR2B subunit selective NMDA receptor antagonists in model systems related to alcoholism.
Nagy
Jozsef
J
Gedeon Richter Ltd., Pharmacological and Drug Safety Research, Budapest 10. P.O.Box 27, H-1475 Hungary. jozsef.nagy@richter.hu
D019973:Alcohol-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D009474:Neurons / Q000187:drug effects; D021122:Protein Subunits / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy; D015854:Up-Regulation
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol