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Enhancement of Antidepressant Potency by a Potentiator of AMPA Receptors

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Abstract

1. AMPA receptor potentiators (ARPs) exhibit antidepressant-like activity in preclinical tests (for example, the forced swim test) that are highly predictive of efficacy in humans. Unlike most currently used antidepressants, ARPs do not elevate extracellular levels of biogenic amines (e.g., 5HT, NE) in prefrontal cortex at doses that are active in the forced swim test.

2. The present series of experiments examined the effects of combining the ARP, LY 392098, with biogenic amine-based antidepressants in the forced swim test. Male, NIH Swiss mice were placed in a cylinder of water and observed for attempted escape behaviors and immobility.

3. LY 392098 dose-dependently decreased immobility as did a range of classical antidepressants. At doses of LY 392098 below those that decreased immobility, this compound significantly increased the potency with which fluoxetine and citalopram (SSRI antidepressants), imipramine (tricyclic antidepressant), duoxetine (norepinephrine/serotonin uptake blocker), nisoxetine (norepinephrine uptake inhibitor), and rolipram (PDE4 inhibitor) decreased immobility in the forced swim test with potency shifts upward of 5-fold (fluoxetine, imipramine, and rolipram). Likewise, ineffective doses of the traditional antidepressants potentiated the effects LY 392098 with shifts in the dose-effect functions that were 10-fold or more for citalopram, fluoxetine, imipramine, and duloxetine.

4. Combined with other evidence for a role of AMPA receptors in the efficacy of antidepressants, the current data suggest that the addition of an ARP may augment the activity and perhaps the onset of the therapeutic effects of biogenic amine and second messenger-based antidepressants.

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References

  • Bai, F., Li, X., Clay, M., Lindstrom, T., and Skolnick, P. (2001). Intra-and interstrain differences in models of “behavioral despair.” Pharmacol. Biochem. Behav. 70:187–192.

    Google Scholar 

  • Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., and Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry. 47:351–354.

    Google Scholar 

  • Borsini, F., and Meli, A. (1988). Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology. 94:147–160.

    Google Scholar 

  • Caldecott-Hazard, S., Morgan, D. G., DeLeon-Jones, F., Overstreet, D. H., and Janowsky, D. (1991). Clinical and biochemical aspects of depressive disorders: II. Transmitter/receptor theories. Synapse 9:251–301.

    Google Scholar 

  • Cryan, J. F., Markou, A., and Lucki, I. (2002). Assessing antidepressant activity in rodents: Recent developments and future needs. Trends Pharmacol. Sci. 23:238–45.

    Google Scholar 

  • Daly, J. (1977). Cyclic Nucleotides in the Nervous System, Plenum Press, New York.

    Google Scholar 

  • Duman, R. S., Heninger, G. R., and Nestler, E. J. (1997). A molecular and cellular theory of depression. Arch. Gen. Psychiatr. 54:597–606.

    Google Scholar 

  • Eckmann, F., Fichte, K., Meya, U., and Sastre-Y-Hernandez, M. (1988). Rolipram in major depression: Results of a double-blind comparative study with amitriptyline. Curr. Ther. Res. 43:291–295.

    Google Scholar 

  • Finney, D. J. (1964). Statistical Methods in Biological Assay, 2nd edn., Hafner, New York.

    Google Scholar 

  • Fleischhacker, W. W., Hinterhuber, H., Bauer, H., Pflug, B., Berner, P., Simhandl, C., Wolf, R., Gerlach, W., Jaklitsch, H., and Sastre-y-Hernandez, M. (1992). A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorders. Neuropsychobiology 26:59–64.

    Google Scholar 

  • Hall, J., Thomas, K. L., and Everitt, B. J. (2000). Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat. Neurosci. 3:533–535.

    Google Scholar 

  • Kent, J. M. (2000). SNaRIs, NaSSAs, and NaRIs: New agents for the treatment of depression. Lancet 355:911–918.

    Google Scholar 

  • Knapp, R. J., Goldenberg, R., Shuck, C., Cecil, A., Watkins, J., Miller, C., Crites, G., and Malatynska, E. (2002). Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur. J. Pharmacol. 440:27–35.

    Google Scholar 

  • Kroczka, B., Branski, P., Palucha, A., Pilc, A., and Nowak, G. (2001). Antidepressant-like properties of zinc in rodent forced swim test. Brain Res. Bull. 15:297–300.

    Google Scholar 

  • Kroczka, B., Zieba, A., Dudek, D., Pilc, A., and Nowak, G. (2000). Zinc exhibits an antidepressant-like effect in the forced swimming test in mice. Pol. J. Pharmacol. 52:403–406.

    Google Scholar 

  • Lauterborn, J. C., Rivera, S., Stinis, C. T., Hayes, V. Y., Isackson, P. J., and Gall, C. M. (1996). Differential effects of protein synthesis inhibition on the activity-dependent expression of BDNF transcripts: evidence for immediate-early gene responses from specific promoters. J. Neurosci. 16:7428–7436.

    Google Scholar 

  • Li, X., Tizzano, J. P., Griffey, K., Clay, M., Lindstrom, T., and Skolnick, P. (2001). Antidepressant-like action of an AMPA receptor potentiator (LY 392098) Neuropharmacology 40:1028–1033.

    Google Scholar 

  • Mackowiak, M., O'Neill, M., Hicks, C., Bleakman, D., and Skolnick, P. (2002). An AMPA receptor potentiator modulates hippocampal expression of BDNF: An in vivo study. Neuropharmacology 43:1–10.

    Google Scholar 

  • Maj, J., Rogoz, Z., Skuza, G., and Sowinska, H. (1992). Effects of MK-801 and antidepressant drugs in the forced swimming test in rats. Eur. Neuropsychopharmacol. 2:37–41.

    Google Scholar 

  • Nibuya, M., Morinobu, S., and Duman, R. S. (1995). Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15:7539–7547.

    Google Scholar 

  • Page, M. E., Detke, M. J., Dalvi, A., Kirby, L. G., and Lucki, I. (1999). Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psychopharmacology (Berl). 147:162–167.

    Google Scholar 

  • Papp, M., and Moryl, E. (1994). Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur. J. Pharmacol. 263:1–7.

    Google Scholar 

  • Papp, M., and Moryl, E. (1996). Antidepressant-like effects of 1-aminocyclopropanecarboxylic acid and D-cycloserine in an animal model of depression. Eur. J. Pharmacol. 316:145–151.

    Google Scholar 

  • Paul, I. A. (2001). Excitatory amino acid signaling, major depression and the actions of antidepressants. Pharmaceut. News 8:33–44.

    Google Scholar 

  • Paul, I. A., Nowak, G., Layer, R. T., Popik, P., and Skolnick, P. (1994). Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. J. Pharmacol. Exp. Ther. 269:95–102.

    Google Scholar 

  • Petrie, R. X., Reid, I. C., and Stewart, C. A. (2000). The N-methyl-D-aspartate receptor, synaptic plasticity, and depressive disorder. Crit. Rev. Pharmacol. Ther. 87:11–25.

    Google Scholar 

  • Porsolt, R. D., Bertin, A., and Jalfre, M. (1977). Behavioral despair in mice: a primary screening test for antidepressants. Arch. Int. Pharmacodyn. Ther. 229:327–336.

    Google Scholar 

  • Porsolt, R. D., and Lenegre, A. (1992). Behavioural models of depression. In Elliott, J., Heal, D. J., and Marsden, C. A., (eds.), Experimental Approaches to Anxiety and Depression, Wiley, London, pp. 73–85.

    Google Scholar 

  • Rogoz, Z., Skuza, G., Maj, J., and Danysz, W. (2002). Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 42:1024–1030.

    Google Scholar 

  • Rossby, S. P., and Sulser, F. (1997). Antidepressants: Beyond the synapse. In Skolnick, P. (ed.), Antidepressants: New Pharmacological Strategies, Humana Press, Totowa, pp. 195–212.

    Google Scholar 

  • Schneider, H. H. (1984). Brain cAMP response to phosphodiesterase inhibitors in rats killed by microwave irradiation or decapitation. Biochemi. Pharmacol. 33:1690–1693.

    Google Scholar 

  • Shirayama, Y., Chen, A. C., Nakagawa, S., Russell, D. S., and Duman, R. S. (2002). Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22:3251–3261.

    Google Scholar 

  • Siuciak, J. A., Lewis, D. R., Wiegand, S. J., and Lindsay, R. M. (1997). Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol. Biochem. Behav. 56:131–137.

    Google Scholar 

  • Skolnick, P. (1999). Antidepressants for the new millennium. Eur. J. Pharmacol. 375:31–41.

    Google Scholar 

  • Skolnick, P., Legutko, B., Li, X., and Bymaster, F. P. (2001). Current perspectives on the development of non-biogenic amine-based antidepressants. Pharmacol. Res. 43:411–43.

    Google Scholar 

  • Snedecor, G. W., and Cochran, W. G. (1967). Statistical Methods, Iowa State University Press, Iowa, pp. 135–171.

    Google Scholar 

  • Svenningsson, P., Tzavara, E. T., Witkin, J., Fienberg, A. A., Nomikos, G. G., and Greengard, P. (2002). Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac). Proc. Natl. Acad. Sci. 99:3182–3187.

    Google Scholar 

  • Trullas, R. (1997). Functional NMDA antagonists: A new class of antidepressant agents. In Skolnick, P. (ed.), Antidepressants: New Pharmacological Strategies, Humana Press, Totowa, pp. 103–124.

    Google Scholar 

  • Willner, P. (1997). Validity, reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation. Psychopharmacology (Berl). 134:319–329.

    Google Scholar 

  • Willner, P., and Papp, M. (1997). Animal models to detect antidepressants: Are new models necessary to detect new agents? In Skolnick, P. (ed.). Antidepressants: New Pharmacological Strategies, Humana Press, Totowa, pp. 213–34.

    Google Scholar 

  • Yilmaz, A., Schulz, D., Aksoy, A., and Canbeyli, R. (2002) Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol Biochem Behav. 71:341–344.

    Google Scholar 

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Li, X., Witkin, J.M., Need, A.B. et al. Enhancement of Antidepressant Potency by a Potentiator of AMPA Receptors. Cell Mol Neurobiol 23, 419–430 (2003). https://doi.org/10.1023/A:1023648923447

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