Alterations in BDNF Protein Concentrations in the Hippocampus do not Explain the Pro-Neurogenic Effect of Citalopram on Adult Neurogenesis

Abstract

Introduction Brain-derived neurotrophic factor (BDNF) has been implicated in the pro-neurogenic effect of selective serotonin reuptake inhibitors. In this study, we used Tph2 ^−/− mice lacking brain serotonin to dissect the interplay between BDNF and the serotonin system in mediating the effects of antidepressant pharmacotherapy on adult neurogenesis in the hippocampus.

Methods Besides citalopram (CIT), we tested tianeptine (TIA), an antidepressant whose mechanism of action is not well understood. Specifically, we examined cell survival and endogenous concentrations of BDNF following daily injection of the drugs.

Results Twenty-one days of CIT, but not of TIA, led to a significant increase in the survival of newly generated cells in the dentate gyrus of wild-type mice, without a significant effect on BDNF protein levels by either treatment. In Tph2 ^−/− mice, adult neurogenesis was consistently increased. Furthermore, Tph2 ^−/− mice showed increased BDNF protein levels, which were not affected by TIA but were significantly reduced by CIT.

Discussion We conclude that the effects of CIT on adult neurogenesis are not explained by changes in BDNF protein concentrations in the hippocampus.

Key words

tryptophan hydroxylase - selective serotonin reuptake inhibitors (SSRIs) - depression - serotonin

• References

• 1 Sangkuhl K, Klein TE, Altman RB. PharmGKB summary: Citalopram pharmacokinetics pathway. Pharmacogenet Genomics 2011; 21: 769-772
• 2 Mennini T, Mocaer E, Garattini S. Tianeptine, a selective enhancer of serotonin uptake in rat brain. Naunyn Schmiedebergs Arch Pharmacol 1987; 336: 478-482
• 3 McEwen BS, Chattarji S, Diamond DM. et al. The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol Psychiatry 2010; 15: 237-249
• 4 Malberg JE, Eisch AJ, Nestler EJ. et al. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104-9110
• 5 Santarelli L, Saxe M, Gross C. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805-809
• 6 Molendijk ML, Bus BA, Spinhoven P. et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: State-trait issues, clinical features and pharmacological treatment. Mol Psychiatry 2011; 16: 1088-1095
• 7 Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16: 2365-2372
• 8 Russo-Neustadt AA, Alejandre H, Garcia C. et al. Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology 2004; 29: 2189-2199
• 9 Alenina N, Kikic D, Todiras M. et al. Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc Natl Acad Sci USA 2009; 106: 10332-10337
• 10 Klempin F, Beis D, Mosienko V. et al. Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci 2013; 33: 8270-8275
• 11 Mosienko V, Bert B, Beis D. et al. Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin. Transl Psychiatry 2012; 2: e122
• 12 Gutknecht L, Popp S, Waider J. et al. Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice. Psychopharmacology (Berl) 2015; 232: 2429-2441
• 13 Mann JJ, Malone KM. Cerebrospinal fluid amines and higher-lethality suicide attempts in depressed inpatients. Biological Psychiatry 1997; 41: 162-171
• 14 Placidi A, Sartori S. Fine needle sampling cytology of palpable breast lesions with immediate reporting. Acta Cytol 2001; 45: 894-896
• 15 Brivio P, Sbrini G, Peeva P. et al. TPH2 deficiency influences neuroplastic mechanisms and alters the response to an acute stress in a sex specific manner. Front Mol Neurosci 2018; 11: 389
• 16 Kronenberg G, Mosienko V, Gertz K. et al. Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin. Eur Arch Psychiatry Clin Neurosci 2016; 266: 281-284
• 17 Migliarini S, Pacini G, Pelosi B. et al. Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation. Mol Psychiatry 2013; 18: 1106-1118
• 18 Kronenberg G, Petermann M, Dormann C. et al. Brain serotonin critically contributes to the biological effects of electroconvulsive seizures. Eur Arch Psychiatry Clin Neurosci 2018; 268: 861-864
• 19 Klempin F, Babu H. De Pietri Tonelli D, et al. Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci 2010; 3: 14
• 20 Mombereau C, Gur TL, Onksen J. et al. Differential effects of acute and repeated citalopram in mouse models of anxiety and depression. Int J Neuropsychopharmacol 2010; 13: 321-334
• 21 Hellweg R, Zueger M, Fink K. et al. Olfactory bulbectomy in mice leads to increased BDNF levels and decreased serotonin turnover in depression-related brain areas. Neurobiol Dis 2007; 25: 1-7
• 22 Jacobsen JP, Mørk A. The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels. Brain Res 2004; 1024: 183-192
• 23 Polacchini A, Metelli G, Francavilla R. et al. A method for reproducible measurements of serum BDNF: comparison of the performance of six commercial assays. Sci Rep 2015; 5: 17989
• 24 Chourbaji S, Hörtnagl H, Molteni R. et al. The impact of environmental enrichment on sex-specific neurochemical circuitries—effects on brain-derived neurotrophic factor and the serotonergic system. Neuroscience 2012; 220: 267-276
• 25 Czeh B, Michaelis T, Watanabe T. et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA 2001; 98: 12796-12801
• 26 Diaz SL, Narboux-Neme N, Trowbridge S. et al. Paradoxical increase in survival of newborn neurons in the dentate gyrus of mice with constitutive depletion of serotonin. Eur J Neurosci 2013; 38: 2650-2658
• 27 Guiard BP, David DJ, Deltheil T. et al. Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype. Int J Neuropsychopharmacol 2008; 11: 79-92
• 28 Deltheil T, Guiard BP, Cerdan J. et al. Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice. Neuropharmacology 2008; 55: 1006-1014
• 29 Nakagawasai O, Yamada K, Odaira T. et al. Liver hydrolysate improves depressive-like behavior in olfactory bulbectomized mice: Involvement of hippocampal neurogenesis through the AMPK/BDNF/CREB pathway. J Pharmacol Sci 2020; 143: 52-55