Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (<i>Danio rerio</i>)
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 enzy...
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/12851 |
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| author | Valentina S. Evsiukova Daria Bazovkina Ekaterina Bazhenova Elizabeth A. Kulikova Alexander V. Kulikov |
| author_facet | Valentina S. Evsiukova Daria Bazovkina Ekaterina Bazhenova Elizabeth A. Kulikova Alexander V. Kulikov |
| author_sort | Valentina S. Evsiukova |
| collection | DOAJ |
| description | 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 (<i>Danio rerio</i>) 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 (<i>Tph2</i>, <i>Slc6a4b</i>, <i>Mao</i>, <i>Htr1aa</i>, <i>Htr2aa</i>) and BDNF-related (<i>Creb</i>, <i>Bdnf</i>, <i>Ntrk2a</i>, <i>Ngfra</i>) 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 <i>Tph2</i> and <i>Htr2aa</i> genes, while pargyline decreased mRNA levels of <i>Slc6a4b</i> and <i>Htr1aa</i> genes. Pargyline reduced <i>Creb</i>, <i>Bdnf</i> and <i>Ntrk2a</i> 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. |
| first_indexed | 2024-03-10T04:53:12Z |
| format | Article |
| id | doaj.art-4b99f3a685fb444986c05eb7268d77a4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:53:12Z |
| publishDate | 2021-11-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4b99f3a685fb444986c05eb7268d77a42023-11-23T02:29:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231285110.3390/ijms222312851Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (<i>Danio rerio</i>)Valentina S. Evsiukova0Daria Bazovkina1Ekaterina Bazhenova2Elizabeth A. Kulikova3Alexander V. Kulikov4Department of Psychoneuropharmacology, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, RussiaDepartment of Behavioral Neurogenomics, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, RussiaDepartment of Genetic Collections of Neural Disorders, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, RussiaDepartment of Psychoneuropharmacology, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, RussiaDepartment of Genetic Collections of Neural Disorders, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, RussiaThe 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 (<i>Danio rerio</i>) 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 (<i>Tph2</i>, <i>Slc6a4b</i>, <i>Mao</i>, <i>Htr1aa</i>, <i>Htr2aa</i>) and BDNF-related (<i>Creb</i>, <i>Bdnf</i>, <i>Ntrk2a</i>, <i>Ngfra</i>) 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 <i>Tph2</i> and <i>Htr2aa</i> genes, while pargyline decreased mRNA levels of <i>Slc6a4b</i> and <i>Htr1aa</i> genes. Pargyline reduced <i>Creb</i>, <i>Bdnf</i> and <i>Ntrk2a</i> 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.https://www.mdpi.com/1422-0067/22/23/12851tryptophan hydroxylase 2serotoninBDNFbrainbehaviorantidepressant resistance |
| spellingShingle | Valentina S. Evsiukova Daria Bazovkina Ekaterina Bazhenova Elizabeth A. Kulikova Alexander V. Kulikov Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (<i>Danio rerio</i>) International Journal of Molecular Sciences tryptophan hydroxylase 2 serotonin BDNF brain behavior antidepressant resistance |
| title | Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (<i>Danio rerio</i>) |
| title_full | Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (<i>Danio rerio</i>) |
| title_fullStr | Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (<i>Danio rerio</i>) |
| title_full_unstemmed | Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (<i>Danio rerio</i>) |
| title_short | Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (<i>Danio rerio</i>) |
| title_sort | tryptophan hydroxylase 2 deficiency modifies the effects of fluoxetine and pargyline on the behavior 5 ht and bdnf systems in the brain of zebrafish i danio rerio i |
| topic | tryptophan hydroxylase 2 serotonin BDNF brain behavior antidepressant resistance |
| url | https://www.mdpi.com/1422-0067/22/23/12851 |
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