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 Genetic Background Underlying 5-HT1A Receptor Functioning Affects the Response to Fluoxetine

2020 ◽  
Vol 21 (22) ◽  
pp. 8784
Author(s):  
Elena M. Kondaurova ◽  
Alexander Ya. Rodnyy ◽  
Tatiana V. Ilchibaeva ◽  
Anton S. Tsybko ◽  
Dmitry V. Eremin ◽  
...  
Keyword(s):  
Genetic Background ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Tryptophan Hydroxylase ◽  
Forced Swim Test ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Tryptophan Hydroxylase 2 ◽  
Protein Levels ◽  
Receptor Mrna ◽  
Fluoxetine Treatment

The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73–110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT1A receptors to chronic 8-OH-DPAT administration and higher 5-HT1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.

The Combined Effects of Amyloidosis and Serotonin Deficiency by Tryptophan Hydroxylase-2 Knockout Impacts Viability of the APP/PS1 Mouse Model of Alzheimer’s Disease

2021 ◽  
pp. 1-18
Author(s):  
Christian Ulrich von Linstow ◽  
Jonas Waider ◽  
Marianne Skov-Skov Bergh ◽  
Marco Anzalone ◽  
Cecilie Madsen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tryptophan Hydroxylase ◽  
Presenilin 1 ◽  
Mrna Levels ◽  
Combined Effects ◽  
Tryptophan Hydroxylase 2 ◽  
Model Of Alzheimer’S Disease ◽  
Serotonin Deficiency ◽  
Targeted Inactivation

Background: A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer’s disease (AD). However, 5-HT’ergic signaling is also suggested to reduce the production of pathogenic amyloid-4β (Aβ). Objective: To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe/presenilin 1 (PS1) ΔE9 transgenic mice. Methods: Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (–/–) were allowed to survive until 6 months old with APP/PS1, Tph2–/–, and wildtype mice. Survival and weight were recorded. Levels of Aβ 42/40/38, soluble APPα (sAβPPα) and sAβPPβ, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aβ were visualized histologically. Results: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aβ 42 and Aβ 40 in neocortex and hippocampus, and with only mild changes of soluble Aβ 42/Aβ 40. However, sAβPPα and sAβPPβ in hippocampus and Aβ 38 and Aβ 40 in cerebrospinal fluid were reduced. 3xTg–/–mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2–/– mice. Microglia clustered around Aβ plaques regardless of genotype. Conclusion: The results suggest that Tph2 inactivation influences AβPP processing, at least in the hippocampus, although levels of Aβ are unchanged. The reduced viability of 3xTg–/–mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice.

Tryptophan hydroxylase 2 in seasonal affective disorder: underestimated perspectives?

2015 ◽  
Vol 26 (6) ◽  
Author(s):  
Alexander V. Kulikov ◽  
Nina K. Popova
Keyword(s):  
Affective Disorder ◽  
Tryptophan Hydroxylase ◽  
Seasonal Affective Disorder ◽  
Recurrent Depression ◽  
Tryptophan Hydroxylase 2 ◽  
System Functioning ◽  
Brain Neurotransmitter ◽  
The Relationship ◽  
Rate Limiting ◽  
The Brain

AbstractSeasonal affective disorder (SAD) is characterized by recurrent depression occurring generally in fall/winter. Numerous pieces of evidence indicate the association of SAD with decreased brain neurotransmitter serotonin (5-HT) system functioning. Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme in 5-HT synthesis in the brain. This paper concentrates on the relationship between TPH2 activity and mood disturbances, the association between human

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