Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice

Gutknecht, Lise; Waider, Jonas; Kraft, Stefanie; Kriegebaum, C.; Holtmann, Æ Bettina; Reif, Andreas; Schmitt, Angelika; Lesch, Klaus‐Peter

doi:10.1007/s00702-008-0096-6

Cited by 159 publications

(153 citation statements)

References 26 publications

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“…(b) Specification of raphe neurons lacking 5-HT synthesis Several in vitro studies showed a morphogenic effect of 5-HT on proliferation, differentiation, migration and survival of neural cells [80][81][82] 11,14). Conserved particularly is the expression of genes specifying a serotonergic phenotype in raphe neurons lacking 5-HT synthesis.…”

Section: Tph2 In Personality Traits Of Negative Emotionality and In Dmentioning

confidence: 99%

“…While perfusion of brain with removal of the residual blood in capillaries resulted in minimal amounts of 5-HT in the rostral raphe region at the lower detection limit (less than 1.2%), it remains possible that a small number of blood components with high 5-HT content, such as platelets or mastocytes, remain trapped in capillaries of brain tissue [14]. Very low brain 5-HT levels were also detected in other Tph2 2/2 mice [21] as well as in Tph1/Tph2 2/2 double KO mice [23].…”

Section: (C) Monoamine Transmitters and Neuronsmentioning

confidence: 99%

“…To explore the question of what traits or neuropsychiatric disorders are attributable to TPH2 dysfunction across the lifespan, mice with targeted inactivation of Tph2 were generated [14], revealing a remarkable phenotypic pleiotropy (figures 1 and 2; table 1).…”

Section: Introductionmentioning

confidence: 99%

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Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Lesch

Araragi

Waider

et al. 2012

Phil. Trans. R. Soc. B

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129

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Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111 -140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581 -604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.Keywords: tryptophan hydroxylase (TPH2); cognition; emotion; impulsivity; aggression; violence INTRODUCTIONNegative emotionality, aggression and antisociality are complex temperamental traits and social behaviours that arise out of multiple causes involving biological and psychological dynamisms and social forces, and different forms of emotional behaviour may each result from different biopsychosocial pathways. The societal implications of aggressiveness, which results in numerous facets of aggressive behaviour and ranges from the establishment of hierarchies and dominance to antisocial behaviour and delinquency, have been examined with preclinical and clinical frameworks.Developmentally inappropriate conduct, aggressiveness and failure in social adjustment represent the most detrimental and harmful long-term outcome of a wide spectrum of neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation.In both humans and animals, the term aggression comprises a variety of behaviours that are heterogeneous for clinical phenomenology and neurobiological features. While the impact of complex cultural variables on behaviour impedes simple extrapolation of animal phenotypes to human traits, clinical observation, experimental paradigms in the laboratory and cluster/ factor-analytic statistics have been used in attempts to subdivide aggression. On the basis of different approaches, hu...

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Section: Tph2 In Personality Traits Of Negative Emotionality and In Dmentioning

confidence: 99%

Section: (C) Monoamine Transmitters and Neuronsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Lesch

Araragi

Waider

et al. 2012

Phil. Trans. R. Soc. B

Self Cite

129

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“…Illustration of biosynthesis of serotonin (blue arrows), the inhibitor action of telotristat etiprate on TPH (red X), conversion of serotonin to 5-hydroxyindole acetic acid and urinary excretion (green arrows), and activating and inhibitory pathways [20,[24][25][26][27][28].…”

Section: Resistance To Somatostatin Analogsmentioning

confidence: 99%

“…Consequently, it does not diminish central serotonin levels, thus avoiding the side effects that it would entail otherwise [27,28,[52][53][54][55].…”

Section: Telotristat Etipratementioning

confidence: 99%

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

et al. 2016

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The carcinoid syndrome represents a set of signs and symptoms associated with neuroendocrine tumors (NETs) that occur primarily when metastases are developed in the liver, resulting in the worsening of quality of life. Serotonin plays a central role in the physiology of carcinoid syndrome by promoting intestinal motility. Somatostatin analogs (SSAs) have widely demonstrated their efficacy as symptomatic relievers of carcinoid syndrome, but this control is ephemeral, being reduced by approximately 50% within the first year. The exact mechanisms of resistance to SSAs are not fully understood, but it is believed that serotonin might be involved. Patients with carcinoid syndrome present with a significant increase in serotonin plasma levels and, consequently, in the soluble urinary metabolite 5‐hydroxyindole acetic acid. Telotristat etiprate is a potent inhibitor of tryptophan hydroxylase, a rate‐limiting enzyme in the synthesis of serotonin, that has demonstrated in the phase III TELESTAR clinical trial a significant improvement in the control of bowel movements in patients with NETs who have carcinoid syndrome and who have progressed to an SSA. Based on these results, telotristat etiprate has emerged as a potential new option in the treatment algorithm of symptomatic control of functioning NETs. However, some issues need to be clarified, such as the safety profile of the drug outside clinical trials, the benefit in quality of life, and the possible impact on tumor growth, as well as its role within sequencing or combination treatment strategies with pre‐existing drugs effective in NET treatment. Implications for Practice: This article reviews the literature about carcinoid syndrome, which affects patients diagnosed with neuroendocrine tumors. Few articles have been published about this syndrome and its pathophysiology. Somatostatin analogs provide symptomatic relief; however, patients may become refractory to this strategy, usually within the first year of treatment. In this context, as an agent with an innovative mechanism of action, telotristat etiprate has demonstrated activity in a phase III trial, and findings may offer a path to an improve quality of life and prolonged survival for certain patients.

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Attention-Deficit/Hyperactivity Disorder Symptoms in Offspring of Mothers With Impaired Serotonin Production

Halmøy¹,

Johansson²,

Winge³

et al. 2010

Archives of General Psychiatry

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Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice

Cited by 159 publications

References 26 publications

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

Attention-Deficit/Hyperactivity Disorder Symptoms in Offspring of Mothers With Impaired Serotonin Production

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