CHRONIC ADMINISTRATION OF IMIPRAMINE AND CITALOPRAM ALTERS THE EXPRESSION OF NMDA RECEPTOR SUBUNIT MESSENGER-RNAS IN MOUSE-BRAIN - A QUANTITATIVE IN-SITU HYBRIDIZATION STUDY

Chronic administration of antidepressants produces region-specific ada ptive changes in the radioligand binding properties of N-methyl-D-aspa rtate (NMDA) receptors. We hypothesized that this effect of chronic an tidepressant administration was owing to an alteration in NMDA recepto r subunit composition. This hypothesis was examined using in situ hybr idization with [S-35]-labeled riboprobes to quantify the impact of chr onic (16 d) injection with either imipramine (15 mg/kg) or citalopram (20 mg/kg) on the levels of transcripts encoding NMDA receptor subunit s in mouse brain. These antidepressants altered the levels of mRNA enc oding the zeta-subunit in a parallel fashion, with both drugs either r educing transcript levels (e.g., in the cortex, cerebellum, thalamus, and striatum) or producing no substantial effects (e.g., hippocampus). In contrast, these antidepressants often produced distinct, region-sp ecific effects on mRNA levels encoding the epsilon family of subunits. For example, citalopram treatment produced widespread reductions in e psilon 1-subunit mRNA levels (e.g., in frontal cortex, CA2 of hippocam pus, and amygdala), whereas imipramine reduced levels of this transcri pt only in the amygdala. Conversely, imipramine treatment produced wid espread reductions in epsilon 2-subunit mRNA levels (e.g., in cortex, CA1-4 of hippocampus, and amygdala), whereas the effects of citalopram on levels of this transcript were largely restricted to amygdala. The se findings indicate that long-term antidepressant treatment produces region-specific changes in expression of transcripts for NMDA receptor subunits, presumably altering NMDA receptor composition. Because subu nit composition determines the physiological and pharmacological prope rties of NMDA receptors, these changes may play a critical role in the therapeutic actions of structurally diverse antidepressants.