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

Jenny C. E. Owen and Peter S. Whitton, The School of Pharmacy, Department of Pharmacology, 29-39 Brunswick Square, London WC1N 1AX, UK.

Current strategies in the treatment of depression are still largely based upon the monoamine theory of the illness. Although many relatively new antidepressants (AD’s) are highly selective for either the 5-HT (selective serotonin reuptake inhibitors; SSRI’s) or NA (selective noradrenaline reuptake inhibitors; SNRI’s) transport sites these drugs are only efficacious in approximately 70-80 % of patients indicating that other factors may be involved. It has been suggested that one mechanism could involve glutamatergic NMDA receptors. NMDA receptor antagonists have been observed to have antidepressant like properties in a number of paradigms of the illness (Skolnick, 1998). We have observed that the tricyclic AD clomipramine (CIM) given chronically decreases NMDA mediated alterations in extracellular 5-HT (Pallotta et al., 2001). We have now studied whether this observation extends to other AD’s and also if the phenomenon is reversible after treatment is discontinued. To do this we have studied extracellular 5-HT in rats using microdialysis.

Male Wistar rats (n = 6-8 per group) were given CIM, the SSRI paroxetine (PAROX) or the SNRI reboxetine (REB; all at 10mg kg-1). Drugs were given i.p. on the day of dialysis or for 14 days prior to dialysis. In the latter groups animals were dialysed at 1, 3 or 14 days after the final dose of AD. Rats were implanted with dialysis probes into the frontal cortex and the following day dialysed. 100μM NMDA or 100mM KCl was infused for 30 min via the dialysis probe. 5-HT was determined using HPLC with electrochemical detection as previously described (Pallotta et al., 2001). Data was subjected to two way analysis of variance followed by Bonferonni’s test.

Acutely, none of the AD’s significantly altered extracellular 5-HT, while NMDA infusion evoked an increase (maximum 250 %, p<0.05). All three AD’s increased extracellular 5-HT after 14 days of treatment by around 3-5 fold, while at the same time the effects of NMDA on extracellular 5-HT in these rats was abolished, although KCl infusion evoked a marked increase indicating that evoked release could still be induced. In vehicle treated rats NMDA infusion still evoked a significant increase in extracellular 5-HT comparable to that after acute vehicle treatment. This situation was unchanged after three days of drug washout with 5-HT levels remaining high and no response to NMDA infusion occurring. After 14 days of antidepressant washout, however, extracellular 5-HT levels in all three AD drug groups was very near to or at basal values. In these groups NMDA infusion now evoked an increase in extracellular 5-HT comparable to that seen in vehicle treated rats.

The present data indicate that chronic treatment with different AD’s attenuates NMDA mediated elevation of extracellular 5-HT and that this is a reversible process. If a reduction in NMDA receptor activity plays a role in AD drug action these could be of possible therapeutic significance.