Intracellular modulation of NMDA receptor function by antipsychotic drugs

The present study deals with the functional interaction of antipsychotic dr ugs and NMDA receptors. We show that both the conventional antipsychotic dr ug haloperidol and the atypical antipsychotic drug clozapine mediate gene e xpression via intracellular regulation of NMDA receptors, albeit to differe nt extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAM P pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser- NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to a lanine, which prevents phosphorylation at both sites, inhibits cAMP-mediate d gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction me chanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefit s as well as side effects of antipsychotic drug treatment.