Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline
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Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline. / Dencker, Ditte; Wörtwein, Gitta; Weikop, Pia; Jeon, Jongrye; Thomsen, Morgane; Sager, Thomas N.; Mørk, Arne; Woldbye, David Paul Drucker; Wess, Jürgen; Fink-Jensen, Anders.
In: Journal of Neuroscience, Vol. 31, No. 16, 2011, p. 5905-8.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline
AU - Dencker, Ditte
AU - Wörtwein, Gitta
AU - Weikop, Pia
AU - Jeon, Jongrye
AU - Thomsen, Morgane
AU - Sager, Thomas N.
AU - Mørk, Arne
AU - Woldbye, David Paul Drucker
AU - Wess, Jürgen
AU - Fink-Jensen, Anders
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Amphetamine
KW - Analysis of Variance
KW - Animals
KW - Behavior, Animal
KW - Central Nervous System Stimulants
KW - Hyperkinesis
KW - Mice
KW - Mice, Knockout
KW - Motor Activity
KW - Muscarinic Agonists
KW - Neurons
KW - Pyridines
KW - Receptor, Muscarinic M4
KW - Thiadiazoles
U2 - 10.1523/JNEUROSCI.0370-11.2011
DO - 10.1523/JNEUROSCI.0370-11.2011
M3 - Journal article
C2 - 21508215
VL - 31
SP - 5905
EP - 5908
JO - The Journal of neuroscience : the official journal of the Society for Neuroscience
JF - The Journal of neuroscience : the official journal of the Society for Neuroscience
SN - 0270-6474
IS - 16
ER -
ID: 33916938