The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat
The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetyl...
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doaj-90099704715d4a1292189ee8ac76edd02020-11-25T00:20:30ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-06-01810.3389/fphar.2017.00279261391The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake RatCraig F. Ferris0Praveen Kulkarni1Jason R. Yee2Mark Nedelman3Inge E. M. de Jong4Department of Psychology, Center for Translational NeuroImaging, Northeastern UniversityBoston, MA, United StatesDepartment of Psychology, Center for Translational NeuroImaging, Northeastern UniversityBoston, MA, United StatesDepartment of Psychology, Center for Translational NeuroImaging, Northeastern UniversityBoston, MA, United StatesEkam ImagingBoston, MA, United StatesDivision of Neurodegeneration, H. Lundbeck A/SValby, DenmarkThe 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.http://journal.frontiersin.org/article/10.3389/fphar.2017.00279/fullserotoninacetylcholineBOLD fMRIcognitionAlzheimer's disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Craig F. Ferris Praveen Kulkarni Jason R. Yee Mark Nedelman Inge E. M. de Jong |
spellingShingle |
Craig F. Ferris Praveen Kulkarni Jason R. Yee Mark Nedelman Inge E. M. de Jong The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat Frontiers in Pharmacology serotonin acetylcholine BOLD fMRI cognition Alzheimer's disease |
author_facet |
Craig F. Ferris Praveen Kulkarni Jason R. Yee Mark Nedelman Inge E. M. de Jong |
author_sort |
Craig F. Ferris |
title |
The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat |
title_short |
The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat |
title_full |
The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat |
title_fullStr |
The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat |
title_full_unstemmed |
The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat |
title_sort |
serotonin receptor 6 antagonist idalopirdine and acetylcholinesterase inhibitor donepezil have synergistic effects on brain activity—a functional mri study in the awake rat |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2017-06-01 |
description |
The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients. |
topic |
serotonin acetylcholine BOLD fMRI cognition Alzheimer's disease |
url |
http://journal.frontiersin.org/article/10.3389/fphar.2017.00279/full |
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