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 N-methyl-d-aspartate (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 of 5 mg/kg. When tested in combination, the antidepressant-like effects of 5 mg/kg imipramine, 20 mg/kg fluoxetine, and 5 mg/kg venlafaxine were potentiated by neramexane (2.5 mg/kg), a dose that alone did not produce a significant effect on the duration of immobility. These effects seemed 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 ED50 values 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, whereas 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 they leave open the question as to whether enhanced BDNF expression is a necessary feature of the antidepressant-like effect.
Footnotes
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This work was supported by a Sponsored Research Agreement to the Institute of Pharmacology, Polish Academy of Sciences, from Merz Pharmaceuticals, and by statutory activity funds of the Institute of Pharmacology, Kraków, Poland.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.103697.
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ABBREVIATIONS: NMDAR-A, N-methyl-d-aspartate receptor antagonist; TST, tail suspension test; BDNF, brain-derived neurotrophic factor; SSC, saline sodium citrate; ANOVA, analysis of variance; MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; LY392098, R,S-N-2-(4-(3-thienyl)phenyl)propyl-2-propanesulfonamide.
- Received February 27, 2006.
- Accepted May 31, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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