Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular dopamine in the frontal cortex of freely moving rats.

NMDA receptors play a role in the aetiology of depression with non-competitive NMDA receptor antagonists such as amantadine showing synergy with conventional antidepressants. To advance a neurochemical rational for these findings, we have studied the effects of administration of amantadine and budipine with the antidepressants reboxetine (REB), paroxetine (PAROX) and clomipramine (CLOM) on extracellular DA in rats using microdialysis. Acutely, amantadine (40 mg/kg) or budipine (10 mg/kg) did not significantly alter extracellular DA. REB (10 mg/kg), PAROX (10 mg/kg) both increased cortical DA while CLOM (10 mg/kg) produced a decrease. When amantadine or budipine was administered 30 min before the antidepressants, DA increases were markedly greater than following the antidepressants alone. Chronically drug effects were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular DA at any time. The three antidepressants elicited a gradual increase in DA which became significant after 7 days and tended to plateau thereafter. When amantadine (20 mg/kg) or budipine (5 mg/kg) was co-administered with the three antidepressants, two differences were seen compared with the antidepressants alone. Firstly, the time required for significant increases in cortical DA was reduced with elevated levels now being observed by 4 days. Secondly, the increase in extracellular DA was greater in these rats throughout the experiment. If increased extracellular DA represents a step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants and possibly enhance their efficacy.

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.

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular 5-HT in the frontal cortex of freely moving rats.

1. Evidence has recently suggested that NMDA receptors may play a role in the aetiology and possible treatment of depression and that weak noncompetitive NMDA receptor antagonists such as amantadine can synergize with conventional antidepressants in a model of the illness. 2. To try to obtain a neurochemical rationale for these findings, we have studied the effects of acute and chronic administration of amantadine or the related drug budipine on cortical release of 5-hydroxytryptamine (5-HT) following the antidepressants reboxitine (REB), paroxetine (PAROX) and clomipramine (CLOM) in freely moving rats by using microdialysis. 3. Acute administration of amantadine (40 mg kg(-1)), budipine (10 mg kg(-1)), REB (10 mg kg(-1)), PAROX (10 mg kg(-1)) or CLOM (10 mg kg(-1)) all failed to significantly alter extracellular 5-HT in the cortex. However, when either amantadine or budipine was administered 30 min prior to any of the three antidepressants, a significant rise in 5-HT was observed. 4. For chronic studies, the effects of the drugs were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular 5-HT at any time point. The three antidepressant drugs all elicited a gradual increase in 5-HT, which became significant after 14 days and tended to plateau thereafter. When either amantadine (20 mg kg(-1)) or budipine (5 mg kg(-1)) was coadministered with any of the three antidepressants, two differences were seen compared with the effects of the antidepressants alone. Firstly, the time required for significant increases in cortical 5-HT was reduced with elevated levels now being observed by 7 days. Secondly, the absolute magnitude of the increase in extracellular 5-HT was markedly greater in these rats from day 7 until the end of the experiment. 5. If, as is widely considered, an increase in extracellular 5-HT represents a critical step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants as well as possibly enhance their efficacy.

Reboxetine modulates norepinephrine efflux in the frontal cortex of the freely moving rat: the involvement of alpha 2 and 5-HT1A receptors.

The effect of reboxetine on norepinephrine (NE) efflux in the frontal cortex of freely moving rats has been studied using in vivo microdialysis. Reboxetine was administered either by injection (10 and 30 mg/kg i.p.) or directly to the frontal cortex via the dialysis probe (10 and 100 microM). To further elucidate the mechanism of action of reboxetine in this region yohimbine (10 microM) was co-infused with reboxetine via the frontal cortex probe. Both routes of administration of reboxetine resulted in a drug-induced, dose-dependent decrease in frontal cortex NE efflux. This effect was reversed following co-infusion of yohimbine, which has been shown to possess both alpha(2)-adrenoceptor antagonist and 5-HT(1A) agonist properties.