Evidence suggests that the mechanism of antidepressant (AD) drug action may be partly dependent on a reduction in NMDA receptor function (Skolnick, 1999). We have observed that long-term treatment with the 5-HT reuptake inhibitor clomipramine elicits a decrease in NMDA receptor function (Pallotta et al., 2001), suggesting that neurochemical effects beyond the basic monoamine theory may be mechanistically significant in AD drug action. Amantadine (AMA) and budipine (BUD) are clinically used compounds which have been found to be weak non-competitive antagonists at the NMDA receptor. We have speculated that by decreasing NMDA receptor function they may potentate AD effects. To study this possibility we have investigated the effects of co-administration of AMA (20-40mg kg^-1) and BUD (5-10 mg kg^-1) with either the selective serotonin reuptake inhibitor paroxetine (PAROX; 10mg kg^-1) or the selective noradrenaline reuptake inhibitor reboxitine (REB; 10mg kg^-1) on extracellular 5-HT in the frontal cortex of freely moving rats.

Experiments were carried out in accordance with the Animals Scientific Procedures Act UK (1986). Male Wistar rats (210-240g) were group housed and had access to food and water ad libitum. Microdialysis was performed as previously described (Whitton et al., 1992) with rats being dialysed the day after probe implantation. Rats were either given drugs on the day of dialysis or chronically for time points up to 21 days. In the latter case the final dose of drug was administered the day before dialysis. Dialysates were analysed for 5-HT as previously described (Whitton et al., 1992). Data were analysed using one way analysis of variance followed by Dunnetts test or by unpaired Students t-test.

Acutely, REB, PAROX, AMA or BUD failed to alter cortical 5-HT. When AMA or BUD were given 30min prior to REB or PAROX a significant increase in cortical 5-HT release was observed. Longterm treatment with AMA or BUD failed to alter extracellular 5-HT at any time point. When REB was given with either of the two NMDA antagonists, by day 4 dialysate 5-HT was significantly increased above both control values and REB given alone. This pattern was broadly maintained up to day 21 of treatment. Similarly, co-administration of PAROX with either AMA or BUD led to significantly greater dialysate 5-HT levels than seen in either saline or PAROX only treated rats by day 7. In these animals, for example, the dialysate figures for 5-HT were (fmol 10μl^-1): controls, 71.6 ± 10.6; PAROX, 103.6 ± 8.6, BUD 69.0 ± 8.3 and PAROX + BUD, 217.3 ± 18.9 (P<0.001 versus all other groups).This pattern was also maintained to the end of the experiment. Only by day 14 and thereafter did REB and PAROX alone significantly increase cortical 5-HT and these increases were less than those seen with the drug combinations.

Our findings indicate both qualitative and quantitative effects of NMDA antagonism on REB and PAROX-induced increases in cortical extracellular 5-HT. As speed of therapeutic onset is an important consideration during AD treatment, the current findings may be relevant in this context. Moreover, the larger increases in extracellular 5-HT seen with the drug combinations may lead to greater clinical efficacy or reduced dosages of ADs.

Pallotta, M., et al. (2001) Neuropharmacology, 57, 294-300
Skolnick, P. (1999) Eur. J. Pharmacol., 375, 31-40
Whitton, P.S., et al. (1992) J. Neurochem., 58, 1573-1575