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BEHAVIORAL PHARMACOLOGY

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

Laboratory of Behavioral Neuroscience (T.K., P.P.) and Department of Pharmacology (B.L.), Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland; Preclinical R&D, Merz Pharmaceuticals, Frankfurt/Main, Germany (W.D.); and Forest Research Institute, Jersey City, New Jersey (G.S.)

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.

Address correspondence to: Dr. Piotr Popik, Behavioral Neuroscience, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St., 31-343 Kraków, Poland. E-mail: nfpopik{at}cyf-kr.edu.pl

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				J. Andreasen, G. Olsen, O Wiborg, and J. Redrobe Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests J Psychopharmacol, September 1, 2009; 23(7): 797 - 804. [Abstract] [PDF]