Involvement of a Subpopulation of Neuronal M4Muscarinic Acetylcholine Receptors in the Antipsychotic-like Effects of the M1/M4Preferring Muscarinic Receptor Agonist Xanomeline

• DOI: 10.1523/jneurosci.0370-11.2011
• Publication Date: 2011-04-20T17:03:10Z
• Authors: Ditte Dencker; Gitta Wörtwein; Pia Weikop; Jongrye Jeon; Morgane Thomsen; Thomas N. Sager; Arne Mørk; David P. D. Woldbye; Jürgen Wess; Anders Fink-Jensen
• Keywords: Mice, Knockout; Neurons; Behavior; Analysis of Variance; Behavior, Animal; Receptor, Muscarinic M4; Animal; Pyridines; Knockout; Hyperkinesis; Motor Activity; Muscarinic Agonists; Muscarinic M4; Amphetamine; Mice; 03 medical and health sciences; 0302 clinical medicine; Thiadiazoles; Animals; Central Nervous System Stimulants; Receptor

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 M4muscarinic 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 M4mAChRs together with D1dopamine receptors seems to be especially important in modulating dopamine-dependent behaviors. Using mutant mice that lack the M4mAChR only in D1dopamine 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 M4mAChRs colocalized with D1dopamine receptors are centrally involved in mediating the antipsychotic-like effects of xanomeline. This is consistent with the hypothesis that activation of the M4mAChR represents a potential target for the future medical treatment of psychosis.