Striatal, Hippocampal, and Cortical Networks Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated Effects of Xanomeline
Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer’s diseases. This is best exemplified by clinical observations with xanomeline, the efficacy of which is thought to be mediated t...
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Published in | ACS chemical neuroscience Vol. 10; no. 3; pp. 1753 - 1764 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
20.03.2019
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Abstract | Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer’s diseases. This is best exemplified by clinical observations with xanomeline, the efficacy of which is thought to be mediated through co-activation of the M1 and M4 muscarinic acetylcholine receptors (mAChRs). Here we examined the impact of treatment with xanomeline and compared it to the actions of selective M1 and M4 mAChR activators on in vivo intracellular signaling cascades in mice, including 3′-5′-cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation and inositol phosphate-1 (IP1) accumulation in the striatum, hippocampus, and prefrontal cortex. We additionally assessed the effects of xanomeline on hippocampal electrophysiological signatures in rats using ex vivo recordings from CA1 (Cornu Ammonis 1) as well as in vivo hippocampal theta. As expected, xanomeline’s effects across these readouts were consistent with activation of both M1 and M4 mAChRs; however, differences were observed across different brain regions, suggesting non-uniform activation of these receptor subtypes in the central nervous system. Interestingly, despite having nearly equal in vitro potency at the M1 and the M4 mAChRs, during in vivo assays xanomeline produced M4-like effects at significantly lower brain exposures than those at which M1-like effects were observed. Our results raise the possibility that clinical efficacy observed with xanomeline was driven, in part, through its non-uniform activation of mAChR subtypes in the central nervous system and, at lower doses, through preferential agonism of the M4 mAChR. |
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AbstractList | Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer's diseases. This is best exemplified by clinical observations with xanomeline, the efficacy of which is thought to be mediated through co-activation of the M1 and M4 muscarinic acetylcholine receptors (mAChRs). Here we examined the impact of treatment with xanomeline and compared it to the actions of selective M1 and M4 mAChR activators on in vivo intracellular signaling cascades in mice, including 3'-5'-cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation and inositol phosphate-1 (IP1) accumulation in the striatum, hippocampus, and prefrontal cortex. We additionally assessed the effects of xanomeline on hippocampal electrophysiological signatures in rats using ex vivo recordings from CA1 (Cornu Ammonis 1) as well as in vivo hippocampal theta. As expected, xanomeline's effects across these readouts were consistent with activation of both M1 and M4 mAChRs; however, differences were observed across different brain regions, suggesting non-uniform activation of these receptor subtypes in the central nervous system. Interestingly, despite having nearly equal in vitro potency at the M1 and the M4 mAChRs, during in vivo assays xanomeline produced M4-like effects at significantly lower brain exposures than those at which M1-like effects were observed. Our results raise the possibility that clinical efficacy observed with xanomeline was driven, in part, through its non-uniform activation of mAChR subtypes in the central nervous system and, at lower doses, through preferential agonism of the M4 mAChR. Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer’s diseases. This is best exemplified by clinical observations with xanomeline, the efficacy of which is thought to be mediated through co-activation of the M1 and M4 muscarinic acetylcholine receptors (mAChRs). Here we examined the impact of treatment with xanomeline and compared it to the actions of selective M1 and M4 mAChR activators on in vivo intracellular signaling cascades in mice, including 3′-5′-cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation and inositol phosphate-1 (IP1) accumulation in the striatum, hippocampus, and prefrontal cortex. We additionally assessed the effects of xanomeline on hippocampal electrophysiological signatures in rats using ex vivo recordings from CA1 (Cornu Ammonis 1) as well as in vivo hippocampal theta. As expected, xanomeline’s effects across these readouts were consistent with activation of both M1 and M4 mAChRs; however, differences were observed across different brain regions, suggesting non-uniform activation of these receptor subtypes in the central nervous system. Interestingly, despite having nearly equal in vitro potency at the M1 and the M4 mAChRs, during in vivo assays xanomeline produced M4-like effects at significantly lower brain exposures than those at which M1-like effects were observed. Our results raise the possibility that clinical efficacy observed with xanomeline was driven, in part, through its non-uniform activation of mAChR subtypes in the central nervous system and, at lower doses, through preferential agonism of the M4 mAChR. |
Author | Moon, Joshua Lazzaro, John T O’Connor, Rebecca E Thorn, Catherine A Harms, John Stark, Eda Butter, Christopher R Popiolek, Michael Edgerton, Jeremy R Bourbonais, Clinton A Steyn, Stefanus J |
AuthorAffiliation | Pharmacokinetics, Dynamics and Metabolism Pfizer Worldwide Research and Development Primary Pharmacology Group Medicine Design Internal Medicine Research Unit |
AuthorAffiliation_xml | – name: – name: Primary Pharmacology Group – name: Medicine Design – name: Pharmacokinetics, Dynamics and Metabolism – name: Internal Medicine Research Unit – name: Pfizer Worldwide Research and Development |
Author_xml | – sequence: 1 givenname: Catherine A surname: Thorn fullname: Thorn, Catherine A – sequence: 2 givenname: Joshua surname: Moon fullname: Moon, Joshua – sequence: 3 givenname: Clinton A surname: Bourbonais fullname: Bourbonais, Clinton A – sequence: 4 givenname: John surname: Harms fullname: Harms, John – sequence: 5 givenname: Jeremy R surname: Edgerton fullname: Edgerton, Jeremy R – sequence: 6 givenname: Eda surname: Stark fullname: Stark, Eda – sequence: 7 givenname: Stefanus J surname: Steyn fullname: Steyn, Stefanus J – sequence: 8 givenname: Christopher R orcidid: 0000-0002-9387-5011 surname: Butter fullname: Butter, Christopher R – sequence: 9 givenname: John T surname: Lazzaro fullname: Lazzaro, John T organization: Pfizer Worldwide Research and Development – sequence: 10 givenname: Rebecca E surname: O’Connor fullname: O’Connor, Rebecca E organization: Pfizer Worldwide Research and Development – sequence: 11 givenname: Michael orcidid: 0000-0001-7372-1982 surname: Popiolek fullname: Popiolek, Michael email: michael.popiolek@gmail.com |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30480428$$D View this record in MEDLINE/PubMed |
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Snippet | Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia... Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia... |
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SubjectTerms | Acetylcholine - metabolism Acetylcholine - pharmacology Animals CA1 Region, Hippocampal - drug effects CA1 Region, Hippocampal - metabolism Corpus Striatum - drug effects Corpus Striatum - metabolism Hippocampus - drug effects Hippocampus - metabolism Muscarinic Agonists - pharmacology Prefrontal Cortex - drug effects Prefrontal Cortex - metabolism Pyridines - pharmacology Receptor, Muscarinic M1 - metabolism Thiadiazoles - pharmacology |
Title | Striatal, Hippocampal, and Cortical Networks Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated Effects of Xanomeline |
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