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

Abstract

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. ) 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 À1 ) or budipine (5 mg kg À1 ) 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.

NMDA receptor/nitrergic system blockage augments antidepressant-like effects of paroxetine in the mouse forced swimming test

“…However, there are scarce data regarding the mechanisms by which NMDA antagonists augment the effects of antidepressants (e.g., paroxetine) in the FST. In this regard, using microdialysis, Owen and Whitton (2005) have interestingly demonstrated that acute administration of noneffective doses of the NMDA antagonist amantadine combined with noneffective doses of various antidepressants including paroxetine, reboxetine, budipine, and clomipramine increases the cortical release of 5-HT in freely moving rats. They also showed that chronic administration of amantadine at different times could increase the 5-HT release evoked by antidepressants and even the time required for significant increases in cortical 5-HT was reduced (Owen and Whitton 2005).…”

“…In this regard, using microdialysis, Owen and Whitton (2005) have interestingly demonstrated that acute administration of noneffective doses of the NMDA antagonist amantadine combined with noneffective doses of various antidepressants including paroxetine, reboxetine, budipine, and clomipramine increases the cortical release of 5-HT in freely moving rats. They also showed that chronic administration of amantadine at different times could increase the 5-HT release evoked by antidepressants and even the time required for significant increases in cortical 5-HT was reduced (Owen and Whitton 2005). Therefore, taking these results together with our present data into consideration, it could be suggested that the antidepressantlike effects of combined noneffective doses of NMDA antagonists and paroxetine may be due to their effects on the central 5-HT release.…”

Enhancement of Antidepressant-Like Effects but Not Brain-Derived Neurotrophic Factor mRNA Expression by the Novel N-Methyl-d-aspartate Receptor Antagonist Neramexane in Mice

“…Owen and Whitton (2005) reported recently that amantadine and budipine (the weak NMDAR-As) given acutely with known antidepressants elevated extracellular serotonin concentration in the frontal cortices of rats and facilitated and potentiated this effect after prolonged treatment. These authors suggested that effects on serotonin concentrations could be due to a number of reasons, including alteration of glutamatergic tone at NMDARs that could facilitate serotonin neurotransmission as well as budipine and amantadine effects on monoamine metabolism.…”

The efficacy of microemulsion-based delivery to improve vitamin E properties: evaluation of the antinociceptive, antioxidant, antidepressant- and anxiolytic-like activities in mice

“…Assuming the close linkage of oxidative stress and the pathophysiology of anxiety, depression, and pain, we evaluated oxidative parameters in the liver, kidney and cerebral cortex of mice exposed to acute and subchronic treatments. Of particular importance, VE‐ME treatment decreases TBARS levels, reducing the lipid peroxidation levels.…”