Document Detail

Involvement of a Subpopulation of Neuronal M4 Muscarinic Acetylcholine Receptors in the Antipsychotic-like Effects of the M1/M4 Preferring Muscarinic Receptor Agonist Xanomeline.
MedLine Citation:
PMID:  21508215     Owner:  NLM     Status:  Publisher    
Disturbances in central dopaminergic neurotransmission are believed to be centrally involved in the pathogenesis of schizophrenia. Central dopaminergic and cholinergic systems interact and the cholinergic muscarinic agonist xanomeline has shown antipsychotic effects in clinical studies. Preclinical studies indicate that the M(4) muscarinic cholinergic receptor subtype (mAChR) modulates the activity of the dopaminergic system and that this specific mAChR subtype is involved in mediating the antipsychotic-like effects of xanomeline. A specific neuronal subpopulation that expresses M(4) mAChRs together with D(1) dopamine receptors seems to be especially important in modulating dopamine-dependent behaviors. Using mutant mice that lack the M(4) mAChR only in D(1) dopamine receptor-expressing cells (D1-M4-KO), we investigated the role of this neuronal population in the antipsychotic-like effects of xanomeline in amphetamine-induced hyperactivity and apomorphine-induced climbing. Interestingly, the antipsychotic-like effects of xanomeline in the two models were almost completely abolished in D1-M4-KO mice, suggesting that M(4) mAChRs colocalized with D(1) dopamine receptors are centrally involved in mediating the antipsychotic-like effects of xanomeline. This is consistent with the hypothesis that activation of the M(4) mAChR represents a potential target for the future medical treatment of psychosis.
Ditte Dencker; Gitta Wörtwein; Pia Weikop; Jongrye Jeon; Morgane Thomsen; Thomas N Sager; Arne Mørk; David P D Woldbye; Jürgen Wess; Anders Fink-Jensen
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Publication Detail:
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  31     ISSN:  1529-2401     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  5905-5908     Citation Subset:  -    
Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, University of Copenhagen, DK-2100 Copenhagen, Denmark, Department of Public Health, University of Copenhagen, DK-1014 Copenhagen, Denmark, Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, Discovery Pharmacology Research, H. Lundbeck A/S, DK-2500 Valby, Denmark, Department of Neuroscience and Pharmacology, University of Copenhagen, DK-2200 Copenhagen, Denmark, and Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, 20892.
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