Renaissance of NMDA receptor antagonists: do they have a role in the pharmacotherapy for alcoholism?

Long-term alcohol exposure leads to the development of alcohol dependence, which is possibly induced by changes in specific neurotransmitter functions. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) type of ionotropic glutamate receptor is a particularly important site of action for ethanol. Ethanol potently and selectively inhibits NMDA receptors (NMDARs) and prolonged ethanol exposure produces a compensatory 'upregulation' of NMDAR functions. These changes are believed to underlie the development of ethanol tolerance and dependence as well as acute and delayed signs of withdrawal. Therefore, negative modulators of NMDARs may be useful agents for the pharmacotherapy of alcoholism. NMDAR antagonists attenuate not only the physical symptoms but also some affective and motivational components of alcohol withdrawal. Encouraging experimental results have been obtained with novel uncompetitive (memantine and neramexane (Merz & Co GmbH/Forest Laboratories Inc)), glycine site and NR2B subunit-selective NMDA antagonists (SSNAs). Recently emerged NR2B SSNAs (CP-101606 (Pfizer Inc), Co-101244 (Pfizer Inc/Purdue Neuroscience Corp/Senju Pharmaceutical Co Ltd), CI-1041 (Purdue Neuroscience Corp/Pfizer Inc) and indole-2-carboxamide derivatives) have demonstrated excellent in vitro potency against withdrawal-induced cytotoxicity. Although in vivo data are few, according to their in vitro efficacy and good tolerability, novel NMDA antagonists, especially the NR2B-selective antagonists, may offer a preferable alternative to the presently available pharmacotherapies for treating alcoholism.