The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [<sup>11</sup>C] Raclopride Binding in Tau Mouse Models of Alzheimer’s Disease
Psychosis that occurs over the course of Alzheimer’s disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing out...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/8/2091 |
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| author | Heidy Jimenez Joseph Carrion Leslie Adrien Adam Wolin John Eun Ezra Cinamon Eric H. Chang Peter Davies An Vo Jeremy Koppel |
| author_facet | Heidy Jimenez Joseph Carrion Leslie Adrien Adam Wolin John Eun Ezra Cinamon Eric H. Chang Peter Davies An Vo Jeremy Koppel |
| author_sort | Heidy Jimenez |
| collection | DOAJ |
| description | Psychosis that occurs over the course of Alzheimer’s disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human–mutant–tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET [<sup>11</sup>C] raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment—on both tau and behavior—that may have relevance to AD and other tauopathies. |
| first_indexed | 2024-03-11T00:06:48Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T00:06:48Z |
| publishDate | 2023-07-01 |
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| series | Biomedicines |
| spelling | doaj.art-b50c03d26a1b4862ac7cfaf05a1423ef2023-11-19T00:19:19ZengMDPI AGBiomedicines2227-90592023-07-01118209110.3390/biomedicines11082091The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [<sup>11</sup>C] Raclopride Binding in Tau Mouse Models of Alzheimer’s DiseaseHeidy Jimenez0Joseph Carrion1Leslie Adrien2Adam Wolin3John Eun4Ezra Cinamon5Eric H. Chang6Peter Davies7An Vo8Jeremy Koppel9The Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USAThe Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USAThe Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USAThe Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USAThe Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USADepartment of Biochemistry, Queens College, Flushing, NY 11355, USAThe Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USAThe Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USAThe Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USAThe Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USAPsychosis that occurs over the course of Alzheimer’s disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human–mutant–tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET [<sup>11</sup>C] raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment—on both tau and behavior—that may have relevance to AD and other tauopathies.https://www.mdpi.com/2227-9059/11/8/2091taupsychosisscopolaminelocomotionAlzheimer’s diseasehopping |
| spellingShingle | Heidy Jimenez Joseph Carrion Leslie Adrien Adam Wolin John Eun Ezra Cinamon Eric H. Chang Peter Davies An Vo Jeremy Koppel The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [<sup>11</sup>C] Raclopride Binding in Tau Mouse Models of Alzheimer’s Disease Biomedicines tau psychosis scopolamine locomotion Alzheimer’s disease hopping |
| title | The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [<sup>11</sup>C] Raclopride Binding in Tau Mouse Models of Alzheimer’s Disease |
| title_full | The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [<sup>11</sup>C] Raclopride Binding in Tau Mouse Models of Alzheimer’s Disease |
| title_fullStr | The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [<sup>11</sup>C] Raclopride Binding in Tau Mouse Models of Alzheimer’s Disease |
| title_full_unstemmed | The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [<sup>11</sup>C] Raclopride Binding in Tau Mouse Models of Alzheimer’s Disease |
| title_short | The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [<sup>11</sup>C] Raclopride Binding in Tau Mouse Models of Alzheimer’s Disease |
| title_sort | impact of muscarinic antagonism on psychosis relevant behaviors and striatal sup 11 sup c raclopride binding in tau mouse models of alzheimer s disease |
| topic | tau psychosis scopolamine locomotion Alzheimer’s disease hopping |
| url | https://www.mdpi.com/2227-9059/11/8/2091 |
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