Received for publication February 27, 2006.
Revised May 18, 2006.
Accepted for publication May 31, 2006.

Enhancement of antidepressant-like effects but not BDNF mRNA expression by the novel NMDA receptor antagonist neramexane in mice

Abstract

Improved efficacy in the treatment of depression may be achieved by the combined use of several antidepressants. In the present study, acute administration of the novel NMDA receptor antagonist, neramexane, as well as the representative antidepressants imipramine, fluoxetine and venlafaxine, shortened the duration of immobility in the mouse tail suspension test with a minimal effective dose (MED) of 5 mg/kg. When tested in combination, the antidepressant-like effects of 5 mg/kg of imipramine, 20 mg/kg of fluoxetine and 5 mg/kg of venlafaxine were potentiated by neramexane (2.5 mg/kg), a dose which alone did not produce a significant effect on the duration of immobility. These effects appeared to be specific because they were not accompanied by significant effects on locomotor activity. The enhanced antidepressant-like activity produced with the different combinations was not synergistic as determined by comparing the theoretical and observed ED50s for each combination. In separate experiments, Northern blot analysis showed that a 14-day treatment with imipramine (10 mg/kg, b.i.d) increased brain-derived neurotrophic factor (BDNF) mRNA expression in the cortex while neramexane (5 mg/kg, b.i.d.) decreased it. Combined treatment produced no effect on BDNF mRNA expression. Mice treated with imipramine or neramexane for 14 days and tested shortly after the last dose demonstrated significant shortening of immobility, and the combined treatment produced an even greater antidepressant-like effect. Together these data support the view that NMDA receptor antagonists enhance the potency of antidepressants, but leave open the question as to whether enhanced BDNF expression is a necessary feature of the antidepressant-like effect.

Key words: BDNF, NMDA, antidepressants, depression, neramexane, tail-suspension test