Antipsychotic drug regulation of AMPA receptor affinity states and GluR1, GluR2 splice variant expression.

We recently reported that chronic administration of antipsychotic drugs dramatically elevated [3H]AMPA binding, with minimal elevation of [3H]CNQX binding in rat brain. The aim of the current study was to examine the mechanism of this effect. Chronic haloperidol minimally increased the total number of binding sites (total Bmax) compared to saline-injected animals. Specifically, haloperidol dramatically increased the proportion of high-affinity-site AMPA receptors (approximately 30% increase) without inducing a significant change in the low-affinity constant. In situ hybridization for flip and flop isoforms of GluR1 and GluR2 (AMPA receptors) was not altered in a pattern or degree that compared to the changes seen in AMPA receptor binding. These findings suggest that the long-term action of antipsychotic drugs may be to regulate AMPA receptor responsiveness to agonist stimulation via posttranscriptional means, and is unlikely to be related to GluR1 or GluR2 splice variant expression. This effect may have relevance to both the therapeutic effects and side effects of antipsychotic drugs in humans.