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Effects of M1 and M4 muscarinic acetylcholine receptor positive allosteric modulators on sleep and cognition in rodents
Author(s) -
Gould Robert W,
Nedelcovych Michael T,
Grannan Michael D,
Bubser Michael,
Wood Michael R,
Lindsley Craig W,
Xiang Zixiu,
Wess Jurgen,
Conn P Jeffrey,
Jones Carrie K
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.661.8
Subject(s) - wakefulness , muscarinic acetylcholine receptor , cognition , cholinergic , psychology , neuroscience , schizophrenia (object oriented programming) , agonist , muscarinic acetylcholine receptor m1 , vigilance (psychology) , cognitive deficit , allosteric modulator , pharmacology , medicine , receptor , cognitive impairment , electroencephalography , psychiatry
Clinically available antipsychotics primarily treat the positive symptoms in schizophrenia, but have little or no effect on the negative symptoms or disruptions in cognition or sleep. Muscarinic cholinergic receptor (mAChR) subtypes mediate aspects of learning, memory and sleep/wakefulness. Recently, the M1/M4‐preferring mAChR agonist xanomeline showed efficacy on the positive symptoms and some cognitive impairments in patients with schizophrenia. In the present studies, we evaluated potential cognitive enhancing and wake promoting effects of xanomeline in comparison with the M1 and M4 selective positive allosteric modulators (PAMs) BCQA and VU0152100, respectively, in rodent sleep and cognition models. Electroencephalography data showed that xanomeline increased wakefulness in rats, similar to acetylcholinesterase inhibitors. Ongoing studies are defining the role of M1 and M4 using BCQA and VU0152100. These ligands are also being evaluated in touch screen cognition assays using M1 and M4 KO mice. While M1 and M4 KO mice exhibited no differences on discrimination or reversal learning tasks compared to wildtypes, alterations in cholinergic activity may provide enhanced efficacy in these tasks. Changes in vigilance during wake and sleep efficiency using M1 and/or M4‐preferring mAChR ligands may provide a new approach for the treatment of sleep and cognitive disruptions in schizophrenia.