Dencker, Ditte;
Wörtwein, Gitta;
Weikop, Pia;
Jeon, Jongrye;
Thomsen, Morgane;
Sager, Thomas N.;
Mørk, Arne;
Woldbye, David P. D.;
Wess, Jürgen;
Fink-Jensen, Anders
Involvement of a Subpopulation of Neuronal M4Muscarinic Acetylcholine Receptors in the Antipsychotic-like Effects of the M1/M4Preferring Muscarinic Receptor Agonist Xanomeline
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Media type:
E-Article
Title:
Involvement of a Subpopulation of Neuronal M4Muscarinic Acetylcholine Receptors in the Antipsychotic-like Effects of the M1/M4Preferring Muscarinic Receptor Agonist Xanomeline
Contributor:
Dencker, Ditte;
Wörtwein, Gitta;
Weikop, Pia;
Jeon, Jongrye;
Thomsen, Morgane;
Sager, Thomas N.;
Mørk, Arne;
Woldbye, David P. D.;
Wess, Jürgen;
Fink-Jensen, Anders
imprint:
Society for Neuroscience, 2011
Published in:The Journal of Neuroscience
Language:
English
DOI:
10.1523/jneurosci.0370-11.2011
ISSN:
0270-6474;
1529-2401
Origination:
Footnote:
Description:
<jats:p>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<jats:sub>4</jats:sub>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<jats:sub>4</jats:sub>mAChRs together with D<jats:sub>1</jats:sub>dopamine receptors seems to be especially important in modulating dopamine-dependent behaviors. Using mutant mice that lack the M<jats:sub>4</jats:sub>mAChR only in D<jats:sub>1</jats:sub>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<jats:sub>4</jats:sub>mAChRs colocalized with D<jats:sub>1</jats:sub>dopamine receptors are centrally involved in mediating the antipsychotic-like effects of xanomeline. This is consistent with the hypothesis that activation of the M<jats:sub>4</jats:sub>mAChR represents a potential target for the future medical treatment of psychosis.</jats:p>