Rogoz Z, Skuza G, Maj J, Danysz W. Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 42: 1024-1030
Institute of Pharmacology, Polish Academy of Sciences, PL 31-343 Kraków, Poland. Neuropharmacology
(Impact Factor: 5.11).
07/2002; 42(8):1024-30. DOI: 10.1016/S0028-3908(02)00055-2
In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA receptor antagonists (amantadine, memantine and neramexane). Most combinations resulted in synergistic (hyperadditive) antidepressive-like effects in the forced swim test. Most interesting was the observation that fluoxetine, which was inactive when given alone, showed a positive effect when combined with amantadine (10 and 20 mg/kg), memantine (2.5 and 5 mg/kg) or neramexane (2.5 and 5 mg/kg). The specificity of these observations is supported by control open field studies, which demonstrated no significant increase, or even a decrease in general locomotion after coadministration of the compounds. The present results suggest that the combination of traditional antidepressant drugs and NMDA receptor antagonists may produce enhanced antidepressive effects, and this is of particular relevance for antidepressant-resistant patients.
Available from: Piotr Wlaź
- "Ghasemi et al.  demonstrated a significant shortening of the total duration of immobility of mice placed in an inescapable situation in the Porsolt's test after a joint administration of the low and sub-therapeutic doses of ifenprodil and paroxetine. The synergistic antidepressant-like effects of co-treatment with memantine or amantadine and imipramine, fluoxetine or venlafaxine were seen by Rogó z ˙ et al.    in the pre-clinical studies. Zinc increased the potency of imipramine and citalopram in both the FST and TST (tail suspension test)   . "
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According to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2–4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10 mg/kg) on the activity of antidepressant agents from diverse pharmacological groups.
The antidepressant-like effect was assessed by the forced swim test in mice.
Ifenprodil potentiated the antidepressant-like effect of imipramine (15 mg/kg) and fluoxetine (5 mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5 mg/kg) or tianeptine (15 mg/kg).
The concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments.
- "In a previous study, curcumin did not increase the locomotor activity in mice or rats as compared to vehicle control, showing that the antidepressant like effect was not due to central nervous stimulation. In addition, the specificity of synergistic interactions between amantadine (an uncompetitive NMDA receptor antagonist) and fluoxetine or imipramine is supported by the control open field test in rats which demonstrated no significant increase, or even a decrease in general locomotion after administration of the compounds alone or in combination. "
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ABSTRACT: This study was designed to study potentiation of fluoxetine's antidepressant effect by curcumin or pindolol. Twenty eight groups of mice (n=8) were used in three sets of experiments. In the first set, 9 groups were subjected to the forced swimming test after being treated intraperitoneally with three vehicles, fluoxetine (5 and 20 mg/kg), curcumin (20 mg/kg), pindolol (32 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). One hour after the test, serum and brain fluoxetine and norfluoxetine levels were measured in mice receiving fluoxetine (5 and 20 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). In the second set, the test was done after pretreatment with p-chlorophenylalanine. In the third set, the locomotor activity was measured. The immobility duration was significantly decreased in fluoxetine (20 mg/kg), curcumin (20 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg) groups. These decreases were reversed with p-chlorophenylalanine. Fluoxetine and norfluoxetine levels were significantly higher in fluoxetine (20 mg/kg) group with no differences in fluoxetine (5 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg) groups. Moreover, drugs failed to alter the locomotor activity indicating absence of central stimulation. In conclusion, curcumin, more than pindolol enhanced the antidepressant effect of a subeffective dose of fluoxetine in mice without increasing its serum or brain levels excluding any pharmacokinetic interaction. Reversal of this potentiation with p-chlorophenylalanine suggests a pharmacodynamic interaction through involvement of presynaptic 5-HT1A receptors.
Available from: Alexandra Sulcova
- "Since then, a growing number of evidence confirms that glutamate neurotransmission plays a crucial role in the neuropathology of the depression. Researchers have found that various types of drugs impairing NMDAR functioning (competitive , non-competitive and uncompetitive antagonists, and allosteric modulators) display antidepressant effects in the preclinical (Layer et al., 1995; Rogóz et al., 2002; Li et al., 2011; Burgdorf et al., 2013; Lapidus et al., 2013; Pilc et al., 2013) as well as in the clinical trials (Zarate et al., 2006, 2012). However, the clinical use of NMDA antagonists in pharmacotherapy of mood disorders is hampered by severe side-effects, particularly by psychotic symptoms in humans (Krystal et al., 1994). "
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A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders.
-3α5β-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not induce significant hyperlocomotion.-We showed that PG displayed anxiolytic-like and antidepressant-like properties.
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