Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility
The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopami...
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MDPI AG
2023-09-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/9/1428 |
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| author | Laoise Casserly Daniel R. Garton Ana Montaño-Rodriguez Jaan-Olle Andressoo |
| author_facet | Laoise Casserly Daniel R. Garton Ana Montaño-Rodriguez Jaan-Olle Andressoo |
| author_sort | Laoise Casserly |
| collection | DOAJ |
| description | The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on <i>Gdnf</i> and its receptors, <i>Gfra1</i> and <i>Ret</i>, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases <i>Gdnf</i> expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors <i>Gfra1</i> and <i>Ret</i>. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults—variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists. |
| first_indexed | 2024-03-10T22:59:54Z |
| format | Article |
| id | doaj.art-fbb213fabf5e4015a23da5c658c35a9a |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T22:59:54Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-fbb213fabf5e4015a23da5c658c35a9a2023-11-19T09:46:48ZengMDPI AGBiomolecules2218-273X2023-09-01139142810.3390/biom13091428Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia SusceptibilityLaoise Casserly0Daniel R. Garton1Ana Montaño-Rodriguez2Jaan-Olle Andressoo3Department of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, FinlandDepartment of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, FinlandDepartment of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, FinlandDepartment of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, FinlandThe increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on <i>Gdnf</i> and its receptors, <i>Gfra1</i> and <i>Ret</i>, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases <i>Gdnf</i> expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors <i>Gfra1</i> and <i>Ret</i>. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults—variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists.https://www.mdpi.com/2218-273X/13/9/1428schizophreniadopamineGDNFGFRa1RETmonoamines |
| spellingShingle | Laoise Casserly Daniel R. Garton Ana Montaño-Rodriguez Jaan-Olle Andressoo Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility Biomolecules schizophrenia dopamine GDNF GFRa1 RET monoamines |
| title | Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility |
| title_full | Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility |
| title_fullStr | Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility |
| title_full_unstemmed | Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility |
| title_short | Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility |
| title_sort | analysis of acute and chronic methamphetamine treatment in mice on gdnf system expression reveals a potential mechanism of schizophrenia susceptibility |
| topic | schizophrenia dopamine GDNF GFRa1 RET monoamines |
| url | https://www.mdpi.com/2218-273X/13/9/1428 |
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