Common genetic variations in human brain-specific tryptophan hydroxylase-2 and response to antidepressant treatment

2008 ◽  
Vol 18 (6) ◽  
pp. 495-506 ◽  
Author(s):  
Mladen Vassilev Tzvetkov ◽  
Jürgen Brockmöller ◽  
Ivar Roots ◽  
Julia Kirchheiner
Keyword(s):  
Human Brain ◽  
Tryptophan Hydroxylase ◽  
Antidepressant Treatment ◽  
Genetic Variations ◽  
Tryptophan Hydroxylase 2

scholarly journals Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (Danio rerio)

2021 ◽  
Vol 22 (23) ◽  
pp. 12851
Author(s):  
Valentina S. Evsiukova ◽  
Daria Bazovkina ◽  
Ekaterina Bazhenova ◽  
Elizabeth A. Kulikova ◽  
Alexander V. Kulikov
Keyword(s):  
Danio Rerio ◽  
Tryptophan Hydroxylase ◽  
Antidepressant Treatment ◽  
Antidepressant Drugs ◽  
Model Organism ◽  
Prolonged Treatment ◽  
Mrna Levels ◽  
Tryptophan Hydroxylase 2 ◽  
Surface Dwelling ◽  
The Brain

The mechanisms of resistance to antidepressant drugs is a key and still unresolved problem of psychopharmacology. Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) play a key role in the therapeutic effect of many antidepressants. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT synthesis in the brain. We used zebrafish (Danio rerio) as a promising model organism in order to elucidate the effect of TPH2 deficiency caused by p-chlorophenylalanine (pCPA) on the alterations in behavior and expression of 5-HT-related (Tph2, Slc6a4b, Mao, Htr1aa, Htr2aa) and BDNF-related (Creb, Bdnf, Ntrk2a, Ngfra) genes in the brain after prolonged treatment with two antidepressants, inhibitors of 5-HT reuptake (fluoxetine) and oxidation (pargyline). In one experiment, zebrafish were treated for 72 h with 0.2 mg/L fluoxetine, 2 mg/L pCPA, or the drugs combination. In another experiment, zebrafish were treated for 72 h with 0.5 mg/L pargyline, 2 mg/L pCPA, or the drugs combination. Behavior was studied in the novel tank diving test, mRNA levels were assayed by qPCR, 5-HT and its metabolite concentrations were measured by HPLC. The effects of interaction between pCPA and the drugs on zebrafish behavior were observed: pCPA attenuated “surface dwelling” induced by the drugs. Fluoxetine decreased mRNA levels of Tph2 and Htr2aa genes, while pargyline decreased mRNA levels of Slc6a4b and Htr1aa genes. Pargyline reduced Creb, Bdnf and Ntrk2a genes mRNA concentration only in the zebrafish treated with pCPA. The results show that the disruption of the TPH2 function can cause a refractory to antidepressant treatment.

scholarly journals Brain serotonin deficiency leads to social communication deficits in mice

2015 ◽  
Vol 11 (3) ◽  
pp. 20150057 ◽  
Author(s):  
D. Beis ◽  
K. Holzwarth ◽  
M. Flinders ◽  
M. Bader ◽  
M. Wöhr ◽  
...  
Keyword(s):  
Tryptophan Hydroxylase ◽  
Sexual Preference ◽  
Brain Serotonin ◽  
Adult Males ◽  
Social Situations ◽  
Tryptophan Hydroxylase 2 ◽  
Social Contacts ◽  
Interaction Partners ◽  
Female Urine ◽  
Serotonin Deficiency

A deficit in brain serotonin is thought to be associated with deteriorated stress coping behaviour, affective disorders and exaggerated violence. We challenged this hypothesis in mice with a brain-specific serotonin depletion caused by a tryptophan hydroxylase 2 (TPH2) deficiency. We tested TPH2-deficient ( Tph2 −/– ) animals in two social situations. As juveniles, Tph2 −/− mice displayed reduced social contacts, whereas ultrasonic vocalizations (USVs) were unchanged within same-sex same-genotype pairings. Interestingly, juvenile females vocalized more than males across genotypes. Sexually naive adult males were exposed to fresh male or female urine, followed by an interaction with a conspecific, and re-exposed to urine. Although Tph2 −/− mice showed normal sexual preference, they were hyper-aggressive towards their interaction partners and did not vocalize in response to sexual cues. These results highlight that central serotonin is essential for prosocial behaviour, especially USV production in adulthood, but not for sexual preference.

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