Summary
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1.
Neurotrophins and serotonin have both been implicated in the pathophysiology of depression and in the mechanisms of antidepressant treatments.
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2.
Brain-derived neurotrophic factor (BDNF) influences the growth and plasticity of serotonergic (5-HT) neurons via the activation of trkB receptor.
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Transgenic mice overexpressing the full-length trkB receptor (TrkB.TK+) and showing increased trkB activity in brain, and their wild type (WT) littermates, were injected with the antidepressant fluoxetine or saline, and analyzed behaviorally in the forced swimming test paradigm and biochemically for the concentrations of brain monoamines and their metabolites.
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4.
The TrkB.TK+ mice displayed increased latency to immobility in the forced swim test, suggesting resistance to behavioral despair.
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5.
Fluoxetine increased the latency to immobility in wild-type mice to a similar level as seen in the trkB.TK+ mice after saline treatment, but had no further behavioral effect in the swimming behavior of the trkB.TK+ mice.
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6.
Only minor differences in the levels of brain monoamines and their metabolites were observed between the transgenic and wild-type mice.
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These data, together with other recent observations, suggest that trkB activation may play a critical role in the behavioral responses to antidepressant drugs in mice.
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References
Castrén, E. (2004). Neurotrophic effects of antidepressant drugs. Curr. Opin. Pharmacol. 4:58–64.
Castrén, E. (2005). Is mood chemistry? Nat. Rev. Neurosci. 6:241–246.
Chourbaji, S., Hellweg, R., Brandis, D., Zorner, B., Zacher, C., Lang, U. E., Henn, F. A., Hortnagl, H., and Gass, P. (2004). Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior. Brain Res. Mol. Brain Res. 121:28–36.
Detke, M. J., Johnson, J., and Lucki, I. (1997). Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp. Clin. Psychopharmacol. 5:107–112.
Drevets, W. C. (2001). Neuroimaging and neuropathological studies of depression: Implications for the cognitive-emotional features of mood disorders. Curr. Opin. Neurobiol. 11:240–249.
Duman, R. S., Heninger, G. R., and Nestler, E. J. (1997). A molecular and cellular theory of depression. Arch. Gen. Psychiatry 54:597–606.
Galter, D., and Unsicker, K. (2000). Sequential activation of the 5-HT1(A) serotonin receptor and TrkB induces the serotonergic neuronal phenotype. Mol. Cell Neurosci. 15:446–455.
Huang, E. J., and Reichardt, L. F. (2003). Trk receptors: Roles in neuronal signal transduction. Annu. Rev. Biochem. 72:609–642.
Koponen, E., Lakso, M., and Castren, E. (2004a). Overexpression of the full-length neurotrophin receptor trkB regulates the expression of plasticity-related genes in mouse brain. Brain Res. Mol. Brain Res. 130:81–94.
Koponen, E., Voikar, V., Riekki, R., Saarelainen, T., Rauramaa, T., Rauvala, H., Taira, T., and Castrén, E. (2004b). Transgenic mice overexpressing the full-length neurotrophin receptor trkB exhibit increased activation of the trkB-PLC gamma pathway, reduced anxiety, and facilitated learning. Mol. Cell Neurosci. 26:166–181.
Lu, B. (2003). BDNF and activity-dependent synaptic modulation. Learn. Mem. 10:86–98.
MacQueen, G. M., Ramakrishnan, K., Croll, S. D., Siuciak, J. A., Yu, G., Young, L. T., and Fahnestock, M. (2001). Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression. Behav. Neurosci. 115:1145–1153.
Mamounas, L. A., Altar, C. A., Blue, M. E., Kaplan, D. R., Tessarollo, L., and Lyons, W. E. (2000). BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J. Neurosci. 20:771–82.
Mamounas, L. A., Blue, M. E., Siuciak, J. A., and Altar, C. A. (1995). Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J. Neurosci. 15:7929–39.
Manji, H. K., Drevets, W. C., and Charney, D. S. (2001). The cellular neurobiology of depression. Nat. Med. 7:541–547.
Mattson, M. P., Maudsley, S., and Martin, B. (2004). BDNF and 5-HT: A dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 27:589–594.
McAllister, A. K., Katz, L. C., and Lo, D. C. (1999). Neurotrophins and synaptic plasticity. Annu. Rev. Neurosci. 22:295–318.
Monteggia, L. M., Barrot, M., Powell, C. M., Berton, O., Galanis, V., Gemelli, T., Meuth, S., Nagy, A., Greene, R. W., and Nestler, E. J. (2004). Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc. Natl. Acad. Sci. USA 101:10827–10832.
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., and Monteggia, L. M. (2002). Neurobiology of depression. Neuron 34:13–25.
Neves-Pereira, M., Mundo, E., Muglia, P., King, N., Macciardi, F., and Kennedy, J. L. (2002). The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: Evidence from a family-based association study. Am. J. Hum. Genet. 71:651–655.
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.
Pang, P. T., Teng, H. K., Zaitsev, E., Woo, N. T., Sakata, K., Zhen, S., Teng, K. K., Yung, W. H., Hempstead, B. L., and Lu, B. (2004). Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306:487–491.
Poo, M. M. (2001). Neurotrophins as synaptic modulators. Nat. Rev. Neurosci. 2:24–32.
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.
Russo-Neustadt, A., Beard, R. C., and Cotman, C. W. (1999). Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacology 21:679–682.
Saarelainen, T., Hendolin, P., Lucas, G., Koponen, E., Sairanen, M., MacDonald, E., Agerman, K., Haapasalo, A., Nawa, H., Aloyz, R., Ernfors, P., and Castrén, E. (2003). Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J. Neurosci. 23:349–357.
Sen, S., Nesse, R. M., Stoltenberg, S. F., Li, S., Gleiberman, L., Chakravarti, A., Weder, A. B., and Burmeister, M. (2003). A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28:397–401.
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.
Siuciak, J. A., Boylan, C., Fritsche, M., Altar, C. A., and Lindsay, R. M. (1996). BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res. 710:11–20.
Siuciak, J. A., Clark, M. S., Rind, H. B., Whittemore, S. R., and Russo, A. F. (1998). BDNF induction of tryptophan hydroxylase mRNA levels in the rat brain. J. Neurosci. Res. 52:149–158.
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.
Sklar, P., Gabriel, S. B., McInnis, M. G., Bennett, P., Lim, Y. M., Tsan, G., Schaffner, S., Kirov, G., Jones, I., Owen, M., Craddock, N., DePaulo, J. R., and Lander, E. S. (2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol. Psychiatry 7:579–593.
Zafra, F., Hengerer, B., Leibrock, J., Thoenen, H., and Lindholm, D. (1990). Activity-dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J. 9:3545–3550.
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Koponen, E., Rantamäki, T., Voikar, V. et al. Enhanced BDNF Signaling is Associated with an Antidepressant-like Behavioral Response and Changes in Brain Monoamines. Cell Mol Neurobiol 25, 973–980 (2005). https://doi.org/10.1007/s10571-005-8468-z
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DOI: https://doi.org/10.1007/s10571-005-8468-z