The DOI matches its Crossref record; 80 of the 80 references it cites were found in a registry or an index.
Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin
Open accessAbstract
Serotonin is a major neurotransmitter in the central nervous system (CNS). Dysregulation of serotonin transmission in the CNS is reported to be related to different psychiatric disorders in humans including depression, impulsive aggression and anxiety disorders. The most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, these drugs are not effective in 20-30% of cases. The causes of this failure as well as the molecular mechanisms involved in the origin of psychological disorders are poorly understood. Biosynthesis of serotonin in the CNS is initiated by tryptophan hydroxylase 2 (TPH2). In this study, we used Tph2-deficient (Tph2(-/-)) mice to evaluate the impact of serotonin depletion in the brain on mouse behavior. Tph2(-/-) mice exhibited increased depression-like behavior in the forced swim test but not in the tail suspension test. In addition, they showed decreased anxiety-like behavior in three different paradigms: elevated plus maze, marble burying and novelty-suppressed feeding tests. These phenotypes were accompanied by strong aggressiveness observed in the resident-intruder paradigm. Despite carrying only one copy of the gene, heterozygous Tph2(+/-) mice showed only 10% reduction in brain serotonin, which was not sufficient to modulate behavior in the tested paradigms. Our findings provide unequivocal evidence on the pivotal role of central serotonin in anxiety and aggression.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat
Pellow, S., Chopin, P., File, S. E., & Briley, M. (1985) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(85)90031-7 · Cited by 5,822
Behavioral despair in mice: a primary screening test for antidepressants.
Porsolt, R. D., Bertin, A., & Jalfre, M. (1977) · PubMed · Cited by 3,320
Synthesis of Serotonin by a Second Tryptophan Hydroxylase Isoform
Walther, D. J., Peter, J.-U., Bashammakh, S., Hörtnagl, H., Voits, M., Fink, H., & Bader, M. (2003) · Science · doi:10.1126/science.1078197 · Cited by 1,570
Self-citationThe ascent of mouse: advances in modelling human depression and anxiety
Cryan, J. F., & Holmes, A. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1825 · Cited by 1,198
The spectrum of behaviors influenced by serotonin
Lucki, I. (1998) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00139-5 · Cited by 1,158
Brain Serotonin Content: Physiological Dependence on Plasma Tryptophan Levels
Fernstrom, J. D., & Wurtman, R. J. (1971) · Science · doi:10.1126/science.173.3992.149 · Cited by 1,016
Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult
Gross, C., Zhuang, X., Stark, K., Ramboz, S., Oosting, R., Kirby, L., Santarelli, L., Beck, S., & Hen, R. (2002) · Nature · doi:10.1038/416396a · Cited by 903
The genetics of depression: A review
Levinson, D. F. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.08.024 · Cited by 855
Early-Life Blockade of the 5-HT Transporter Alters Emotional Behavior in Adult Mice
Ansorge, M. S., Zhou, M., Lira, A., Hen, R., & Gingrich, J. A. (2004) · Science · doi:10.1126/science.1101678 · Cited by 817
A unique central tryptophan hydroxylase isoform
Walther, D. J., & Bader, M. (2003) · Biochemical Pharmacology · doi:10.1016/s0006-2952(03)00556-2 · Cited by 751
Self-citationYadav, V. K., Oury, F., Suda, N., Liu, Z.-W., Gao, X.-B., Confavreux, C., Klemenhagen, K. C., Tanaka, K. F., Gingrich, J. A., Guo, X. E., et al. (2009) · Cell · doi:10.1016/j.cell.2009.06.051 · Cited by 661
Cryan, J. F., & Mombereau, C. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001457 · Cited by 616
Overview of the Genetics of Major Depressive Disorder
Lohoff, F. W. (2010) · Current Psychiatry Reports · doi:10.1007/s11920-010-0150-6 · Cited by 498
Evaluation of marble-burying behavior as a model of anxiety
Njung'e, K., & Handley, S. L. (1991) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(91)90590-x · Cited by 487
Lopez-Munoz, F., & Alamo, C. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209788168001 · Cited by 476
Loss-of-Function Mutation in Tryptophan Hydroxylase-2 Identified in Unipolar Major Depression
Zhang, X., Gainetdinov, R. R., Beaulieu, J.-M., Sotnikova, T. D., Burch, L. H., Williams, R. B., Schwartz, D. A., Krishnan, K. R. R., & Caron, M. G. (2005) · Neuron · doi:10.1016/j.neuron.2004.12.014 · Cited by 473
A trans-dimensional approach to the behavioral aspects of depression
Bessa, J. M. (2009) · Frontiers in Behavioral Neuroscience · doi:10.3389/neuro.08.001.2009 · Cited by 469
Hendricks, T. J., Fyodorov, D. V., Wegman, L. J., Lelutiu, N. B., Pehek, E. A., Yamamoto, B., Silver, J., Weeber, E. J., Sweatt, J. D., & Deneris, E. S. (2003) · Neuron · doi:10.1016/s0896-6273(02)01167-4 · Cited by 459
Lira, A., Zhou, M., Castanon, N., Ansorge, M. S., Gordon, J. A., Francis, J. H., Bradley-Moore, M., Lira, J., Underwood, M. D., Arango, V., et al. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00696-6 · Cited by 391
Aggressive Behavior, Increased Accumbal Dopamine, and Decreased Cortical Serotonin in Rats
van Erp, A. M. M., & Miczek, K. A. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-24-09320.2000 · Cited by 380
Role of GSK3β in behavioral abnormalities induced by serotonin deficiency
Beaulieu, J.-M., Zhang, X., Rodriguiz, R. M., Sotnikova, T. D., Cools, M. J., Wetsel, W. C., Gainetdinov, R. R., & Caron, M. G. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711496105 · Cited by 368
Cognitive and neurobiological mechanisms of alcohol-related aggression
Heinz, A. J., Beck, A., Meyer-Lindenberg, A., Sterzer, P., & Heinz, A. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3042 · Cited by 368
Growth retardation and altered autonomic control in mice lacking brain serotonin
Alenina, N., Kikic, D., Todiras, M., Mosienko, V., Qadri, F., Plehm, R., Boyé, P., Vilianovitch, L., Sohr, R., Tenner, K., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810793106 · Cited by 347
Self-citationBenzodiazepines: Anxiety-Reducing Activity by Reduction of Serotonin Turnover in the Brain
Wise, C. D., Berger, B. D., & Stein, L. (1972) · Science · doi:10.1126/science.177.4044.180 · Cited by 339
Zill, P., Baghai, T. C., Zwanzger, P., Schüle, C., Eser, D., Rupprecht, R., Möller, H.-J., Bondy, B., & Ackenheil, M. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001525 · Cited by 323
Holmes, A., Li, Q., Murphy, D. L., Gold, E., & Crawley, J. N. (2003) · Genes, Brain and Behavior · doi:10.1046/j.1601-1848.2003.00050.x · Cited by 313
Placidi, G. P. A., Oquendo, M. A., Malone, K. M., Huang, Y.-Y., Ellis, S. P., & Mann, J. J. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01170-2 · Cited by 288
Savelieva, K. V., Zhao, S., Pogorelov, V. M., Rajan, I., Yang, Q., Cullinan, E., & Lanthorn, T. H. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003301 · Cited by 265
Accumbal dopamine and serotonin in anticipation of the next aggressive episode in rats
Ferrari, P. F., Van Erp, A. M. M., Tornatzky, W., & Miczek, K. A. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02447.x · Cited by 256
Intra- and interstrain differences in models of “behavioral despair”
Bai, F., Li, X., Clay, M., Lindstrom, T., & Skolnick, P. (2001) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(01)00599-8 · Cited by 250
Correlations between aminergic metabolites simultaneously obtained from human CSF and brain
Stanley, M., Traskman-Bendz, L., & Dorovini-Zis, K. (1985) · Life Sciences · doi:10.1016/0024-3205(85)90242-5 · Cited by 246
CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence.
Brown, G. L., & Linnoila, M. (1990) · PubMed · Cited by 241
Coccaro, E. F. (1992) · International Clinical Psychopharmacology · doi:10.1097/00004850-199200710-00001 · Cited by 220
Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland
Patel, P. D., Pontrello, C., & Burke, S. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2003.09.002 · Cited by 217
Genetics of human aggressive behaviour
Craig, I. W., & Halton, K. E. (2009) · Human Genetics · doi:10.1007/s00439-009-0695-9 · Cited by 213 · cited 1×
“different polymorphisms of genes involved in the central serotonin synthesis and transmission are associated with various psychological abnormalities such as depression, anxiety disorders(18) and aggression.(19,20) Moreover, differ-”
Evidence That Serotonin Has a Role in Brain Function
BRODIE, B. B., PLETSCHER, A., & SHORE, P. A. (1955) · Science · doi:10.1126/science.122.3177.968 · Cited by 211
O’Leary, O. F., Bechtholt, A. J., Crowley, J. J., Hill, T. E., Page, M. E., & Lucki, I. (2007) · Psychopharmacology · doi:10.1007/s00213-007-0728-9 · Cited by 177
Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice
Gutknecht, L., Waider, J., Kraft, S., Kriegebaum, C., Holtmann, B., Reif, A., Schmitt, A., & Lesch, K.-P. (2008) · Journal of Neural Transmission · doi:10.1007/s00702-008-0096-6 · Cited by 173
Stanley, B., Molcho, A., Stanley, M., Winchel, R., Gameroff, M. J., Parsons, B., & Mann, J. J. (2000) · American Journal of Psychiatry · doi:10.1176/appi.ajp.157.4.609 · Cited by 155
Jennings, K. A., Loder, M. K., Sheward, W. J., Pei, Q., Deacon, R. M. J., Benson, M. A., Olverman, H. J., Hastie, N. D., Harmar, A. J., Shen, S., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5356-05.2006 · Cited by 153
Sakowski, S. A., Geddes, T. J., Thomas, D. M., Levi, E., Hatfield, J. S., & Kuhn, D. M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.02.047 · Cited by 152
Drugan, R. C., Morrow, A. L., Weizman, R., Weizman, A., Deutsch, S. I., Crawley, J. N., & Paul, S. M. (1989) · Brain Research · doi:10.1016/0006-8993(89)90938-4 · Cited by 150
Vmat2 Heterozygous Mutant Mice Display a Depressive-Like Phenotype
Fukui, M., Rodriguiz, R. M., Zhou, J., Jiang, X. “., Phillips, L. E., Caron, M. G., & Wetsel, W. C. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4388-06.2007 · Cited by 150
Kiyasova, V., Fernández, S. P., Lainé, J., Stankovski, L., Muzerelle, A., Doly, S., & Gaspar, P. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4080-10.2011 · Cited by 148
Liu, Y., Jiang, Y., Si, Y., Kim, J., Chen, Z., & Rao, Y. (2011) · Nature · doi:10.1038/nature09822 · Cited by 140
Enhanced contextual fear memory in central serotonin-deficient mice
Dai, J., Han, H., Tian, M., Cao, J., Xiu, J., Song, N., Huang, Y., Xu, T., Ding, Y., & Xu, L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801329105 · Cited by 136
Dietary Amino Acids and Brain Serotonin Function; Implications for Stress-Related Affective Changes
Markus, C. R. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8039-9 · Cited by 132
Briley, M., Chopin, P., & Moret, C. (1990) · Psychopharmacology · doi:10.1007/bf02244124 · Cited by 127
Neal, K., Parry, L. J., & Bornstein, J. C. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.160416 · Cited by 118
Kulikov, A. V., Osipova, D. V., Naumenko, V. S., & Popova, N. K. (2005) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2005.00145.x · Cited by 116
Bogaert, A. V. D., Sleegers, K., Zutter, S. D., Heyrman, L., Norrback, K., Adolfsson, R., Broeckhoven, C. V., & Del‐Favero, J. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.10.1103 · Cited by 114
Gavioli, E. C., Vaughan, C. W., Marzola, G., Guerrini, R., Mitchell, V. A., Zucchini, S., de Lima, T. C. M., Rae, G. A., Salvadori, S., Regoli, D. C., et al. (2004) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-004-0939-0 · Cited by 103
Aggression: the testosterone-serotonin link.
Birger, M., Swartz, M., Cohen, D., Alesh, Y., Grishpan, C., & Kotelr, M. (2003) · PubMed · Cited by 101
Zhao, S., Edwards, J., Carroll, J. C., Wiedholz, L. M., Millstein, R. A., Jaing, C. J., Murphy, D. L., Lanthorn, T. H., & Holmes, A. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.01.049 · Cited by 99
Pharmacological control of aggressive behavior in mice
Valzelli, L., Giacalone, E., & Garattini, S. K. (1967) · European Journal of Pharmacology · doi:10.1016/0014-2999(67)90040-4 · Cited by 96
Molecular genetics of anxiety in mice and men
Hovatta, I., & Barlow, C. (2008) · Annals of Medicine · doi:10.1080/07853890701747096 · Cited by 92
Neurochemical Differences between Two Strains of Mice
Maas, J. W. (1962) · Science · doi:10.1126/science.137.3530.621 · Cited by 92
Zill, P., Büttner, A., Eisenmenger, W., Bondy, B., & Ackenheil, M. (2003) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2003.10.002 · Cited by 89
Serotonin function and antiaggressive response to fluoxetine: A pilot study
Coccaro, E. F., Kavoussi, R. J., & Hauger, R. L. (1997) · Biological Psychiatry · doi:10.1016/s0006-3223(97)00309-0 · Cited by 88
In search of the mode of action of antidepressants 5-HTP/tyrosine mixtures in depressions
Vanpraag, H. (1983) · Neuropharmacology · doi:10.1016/0028-3908(83)90193-4 · Cited by 86
Narboux‐Nême, N., Sagné, C., Doly, S., Diaz, S. L., Martin, C. B. P., Angenard, G., Martres, M., Giros, B., Hamon, M., Lanfumey, L., et al. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.142 · Cited by 86
Zepf, F. D., Stadler, C., Demisch, L., Schmitt, M., Landgraf, M., & Poustka, F. (2007) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.896 · Cited by 78
Tryptophan Hydroxylase as Novel Target for the Treatment of Depressive Disorders
Matthes, S., Mosienko, V., Bashammakh, S., Alenina, N. V., & Bäder, M. (2010) · Pharmacology · doi:10.1159/000279322 · Cited by 78
Self-citationZalsman, G., Patya, M., Frisch, A., Ofek, H., Schapir, L., Blum, I., Harell, D., Apter, A. S., Weizman, A., & Tyano, S. (2010) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2010.518628 · Cited by 75
Neurochemical Differences between two Strains of Mice
Maas, J. W. (1963) · Nature · doi:10.1038/197255a0 · Cited by 75
Inside the minds of mice and men
Baker, M. (2011) · Nature · doi:10.1038/475123a · Cited by 66
Consistent evidence for a biological subtype of depression characterized by low CSF monoamine levels
Gibbons, R. D., & Davis, J. M. (1986) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1986.tb06219.x · Cited by 64
Schaefer, T. L., Vorhees, C. V., & Williams, M. T. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.09.059 · Cited by 60
Anxiolytic-like effects of median raphe nucleus lesion in the elevated T-maze
Andrade, T. G. C. S., de Macedo, C. E. A., Zangrossi, H., & Graeff, F. G. (2003) · Behavioural Brain Research · doi:10.1016/j.bbr.2003.10.036 · Cited by 60
Thomas, D. M., Angoa‐Pérez, M., Francescutti, D. M., Shah, M. M., & Kuhn, D. M. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06950.x · Cited by 59
The Neurobiology of Tryptophan Depletion in Depression: Effects of Intravenous Tryptophan Infusion
Price, L. H., Malison, R. T., McDougle, C. J., Pelton, G. H., & Heninger, G. R. (1998) · Biological Psychiatry · doi:10.1016/s0006-3223(97)00284-9 · Cited by 57
Critchley, M. A. E., Njung'e, K., & Handley, S. L. (1992) · Psychopharmacology · doi:10.1007/bf02244819 · Cited by 57
Siesser, W. B., Zhang, X., Jacobsen, J. P. R., Sotnikova, T. D., Gainetdinov, R. R., & Caron, M. G. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.06.035 · Cited by 56
Redrobe, J. P., & Bourin, M. (1998) · Psychopharmacology · doi:10.1007/s002130050663 · Cited by 56
Acute tryptophan depletion: a method of studying antidepressant action.
Miller, H., Delgado, P. L., Salomon, R. M., Licinio, J., Barr, L. C., & Charney, D. S. (1992) · PubMed · Cited by 52
O’Leary, O. F., Bechtholt, A. J., Crowley, J. J., Valentino, R. J., & Lucki, I. (2006) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2006.06.012 · Cited by 46
Serotonergic Contribution to Boys' Behavioral Regulation
Nantel‐Vivier, A., Pihl, R. O., Young, S. N., Parent, S., Bélanger, S. A., Sutton, R. S., Dubois, M.-E., Tremblay, R. E., & Séguin, J. R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020304 · Cited by 18
Behavioral alteration in the adult rats prenatally exposed to para-chlorophenylalanine
Vataeva, L. A., Кудрин, В. С., Vershinina, E. A., Mosin, V. M., Tyulkova, E. I., & Otellin, V. A. (2007) · Brain Research · doi:10.1016/j.brainres.2007.06.056 · Cited by 16
Vataeva, L. A., Кудрин, В. С., Vershinina, E. A., Mosin, V. M., Tyulkova, E. I., & Otellin, V. A. (2008) · Brain Research · doi:10.1016/j.brainres.2008.07.064 · Cited by 12
Cited by
The neurobiology of aggression and violence
Rosell, D. R., & Siever, L. J. (2015) · CNS Spectrums · doi:10.1017/s109285291500019x · Cited by 440
Singh, M. (2014) · Frontiers in Psychology · doi:10.3389/fpsyg.2014.00925 · Cited by 337
Albert, P. R., Vahid-Ansari, F., & Luckhart, C. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00199 · Cited by 321
Embracing diversity in the 5-HT neuronal system
Okaty, B. W., Commons, K. G., & Dymecki, S. M. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0151-3 · Cited by 319
Serotonin is required for exercise-induced adult hippocampal neurogenesis
Klempin, F., Beis, D., Mosienko, V., Kempermann, G., Bader, M., & Alenina, N. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.5855-12.2013 · Cited by 235
Self-citation
Metadata
- Authors
- Mosienko, V, Bert, B., Beis, D., Matthes, S., Fink, H., Bader, M., & Alenina, N.
- Venue
- Translational Psychiatry
- Published
- 2012-05-29
- Volume
- 2
- Issue
- 5
- Pages
- e122-e122
- ISSN
- 2158-3188 (ISSN-L)
- OpenAlex
- W2012597831
- Cited by
- 269
- References
- 80
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- gold
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.