Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors
Abstract Multiple sclerosis is a disease characterised by axonal demyelination in the central nervous system (CNS). The atypical antipsychotic drug clozapine attenuates experimental autoimmune encephalomyelitis (EAE), a mouse model used to study multiple sclerosis, but the precise mechanism is unkno...
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2021-02-01
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doaj-1fc8228af1f0439d8a8f71c4d574ac282021-02-07T12:33:01ZengNature Publishing GroupScientific Reports2045-23222021-02-0111111310.1038/s41598-021-82667-6Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptorsKatharina Robichon0Sven Sondhauss1T. William Jordan2Robert A. Keyzers3Bronwen Connor4Anne C. La Flamme5School of Biological Sciences, Victoria University of WellingtonSchool of Biological Sciences, Victoria University of WellingtonSchool of Biological Sciences, Victoria University of WellingtonCentre for Biodiscovery, Victoria University of WellingtonDepartment of Pharmacology and Clinical Pharmacology, Centre for Brain Research, University of AucklandSchool of Biological Sciences, Victoria University of WellingtonAbstract Multiple sclerosis is a disease characterised by axonal demyelination in the central nervous system (CNS). The atypical antipsychotic drug clozapine attenuates experimental autoimmune encephalomyelitis (EAE), a mouse model used to study multiple sclerosis, but the precise mechanism is unknown and could include both peripheral and CNS–mediated effects. To better understand where clozapine exerts its protective effects, we investigated the tissue distribution and localisation of clozapine using matrix-assisted laser desorption ionization imaging mass spectrometry and liquid chromatography-mass spectrometry. We found that clozapine was detectable in the brain and enriched in specific brain regions (cortex, thalamus and olfactory bulb), but the distribution was not altered by EAE. Furthermore, although not altered in other organs, clozapine levels were significantly elevated in serum during EAE. Because clozapine antagonises dopamine receptors, we analysed dopamine levels in serum and brain as well as dopamine receptor expression on brain-resident and infiltrating immune cells. While neither clozapine nor EAE significantly affected dopamine levels, we observed a significant downregulation of dopamine receptors 1 and 5 and up-regulation of dopamine receptor 2 on microglia and CD4+-infiltrating T cells during EAE. Together these findings provide insight into how neuroinflammation, as modelled by EAE, alters the distribution and downstream effects of clozapine.https://doi.org/10.1038/s41598-021-82667-6 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Katharina Robichon Sven Sondhauss T. William Jordan Robert A. Keyzers Bronwen Connor Anne C. La Flamme |
spellingShingle |
Katharina Robichon Sven Sondhauss T. William Jordan Robert A. Keyzers Bronwen Connor Anne C. La Flamme Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors Scientific Reports |
author_facet |
Katharina Robichon Sven Sondhauss T. William Jordan Robert A. Keyzers Bronwen Connor Anne C. La Flamme |
author_sort |
Katharina Robichon |
title |
Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors |
title_short |
Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors |
title_full |
Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors |
title_fullStr |
Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors |
title_full_unstemmed |
Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors |
title_sort |
localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-02-01 |
description |
Abstract Multiple sclerosis is a disease characterised by axonal demyelination in the central nervous system (CNS). The atypical antipsychotic drug clozapine attenuates experimental autoimmune encephalomyelitis (EAE), a mouse model used to study multiple sclerosis, but the precise mechanism is unknown and could include both peripheral and CNS–mediated effects. To better understand where clozapine exerts its protective effects, we investigated the tissue distribution and localisation of clozapine using matrix-assisted laser desorption ionization imaging mass spectrometry and liquid chromatography-mass spectrometry. We found that clozapine was detectable in the brain and enriched in specific brain regions (cortex, thalamus and olfactory bulb), but the distribution was not altered by EAE. Furthermore, although not altered in other organs, clozapine levels were significantly elevated in serum during EAE. Because clozapine antagonises dopamine receptors, we analysed dopamine levels in serum and brain as well as dopamine receptor expression on brain-resident and infiltrating immune cells. While neither clozapine nor EAE significantly affected dopamine levels, we observed a significant downregulation of dopamine receptors 1 and 5 and up-regulation of dopamine receptor 2 on microglia and CD4+-infiltrating T cells during EAE. Together these findings provide insight into how neuroinflammation, as modelled by EAE, alters the distribution and downstream effects of clozapine. |
url |
https://doi.org/10.1038/s41598-021-82667-6 |
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