Chronic treatment with antidepressant drugs reversibly alters NMDA mediated regulation of extracellular 5-HT in rat frontal cortex

Treatment of depression is largely based upon the monoamine theory of the illness. However, current therapies are only efficacious in 70-80% of patients indicating that other factors are involved. One mechanism could involve glutamatergic NMDA receptors since NMDA receptor antagonists have antidepressant like properties in paradigms of the illness. We have observed that the tricyclic clomipramine given chronically decreases NMDA mediated alterations in extracellular 5-hydroxytryptamine (5-HT). We have now studied whether this observation extends to other antidepressant drugs (AD's), reboxetine and parxoetine and also if the phenomenon is reversible after treatment is discontinued. To do this we have studied cortical extracellular 5-HT in rats using microdialysis. Acutely, none of the AD's altered extracellular 5-HT, while 100 microM NMDA infusion evoked an increase. All three AD's increased extracellular 5-HT after 14 days of treatment, however, at the same time the effects of NMDA on extracellular 5-HT were abolished. In vehicle only treated rats NMDA infusion still evoked a significant increase in extracellular 5-HT. This situation was unchanged after 3 days of drug washout with 5-HT levels remaining high and no response to NMDA infusion occurred. After 14 days of antidepressant washout, however, extracellular 5-HT levels in all three AD drug groups were around basal values. In these groups NMDA infusion now evoked an increase in extracellular 5-HT comparable to that seen in vehicle treated rats. If a reduction in NMDA receptor activity plays a role in AD drug action these observations could be of possible therapeutic significance.