ANTIPSYCHOTIC DRUG REGULATION OF AMPA RECEPTOR AFFINITY STATES AND GLUR1, GLUR2 SPLICE VARIANT EXPRESSION

We recently reported that chronic administration of antipsychotic drug s dramatically elevated [H-3]AMPA binding, with minimal elevation of [ H-3]CNQX binding in rat brain. The aim of the current study was to exa mine the mechanism of this effect. Chronic haloperidol minimally incre ased the total number of binding sites (total B-max) compared to salin e-injected animals. Specifically, haloperidol dramatically increased t he proportion of high-affinity-site AMPA receptors (approximate to 30% increase) without inducing a significant change in the low-affinity c onstant. In situ hybridization for flip and flop isoforms of GluR1 and GluR2 (AMPA receptors) was not altered in a pattern or degree that co mpared to the changes seen in AMPA receptor binding. These findings su ggest that the long-term action of antipsychotic drugs may be to regul ate AMPA receptor responsiveness to agonist stimulation via posttransc riptional means, and is unlikely to be related to GluR1 or GluR2 splic e variant expression. This effect may have relevance to both the thera peutic effects and side effects of antipsychotic drugs in humans. (C) 1998 Wiley-Liss, Inc.