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Role of muscarinic receptors in the activity of N-desmethylclozapine: reversal of hyperactivity in the phospholipase C knockout mouse

Gray, Laura, McOmish, Caitlin, Scarr, Elizabeth, Dean, Brian and Hannan, Anthony J. 2008, Role of muscarinic receptors in the activity of N-desmethylclozapine: reversal of hyperactivity in the phospholipase C knockout mouse, Behavioural pharmacology, vol. 19, no. 5-6, pp. 543-547, doi: 10.1097/FBP.0b013e32830c3669.

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Title Role of muscarinic receptors in the activity of N-desmethylclozapine: reversal of hyperactivity in the phospholipase C knockout mouse
Author(s) Gray, Laura
McOmish, Caitlin
Scarr, Elizabeth
Dean, Brian
Hannan, Anthony J.
Journal name Behavioural pharmacology
Volume number 19
Issue number 5-6
Start page 543
End page 547
Total pages 5
Publisher Lippincott Williams & Wilkins
Place of publication Philadelphia, Pa.
Publication date 2008-09
ISSN 0955-8810
Summary Activity of the cholinergic muscarinic system is associated with modulation of locomotor activity, although the precise mechanism remains unclear. The phospholipase C-[beta]1 knockout mouse displays both M1 muscarinic receptor dysfunction and a hyperactive locomotor phenotype. This mouse serves as an ideal model for the analysis of muscarinic modulation of locomotor activity. The clozapine metabolite N-desmethylclozapine (NDMC) has shown some promise as an alternative or adjunct treatment for psychotic disorders. NDMC shows strong muscarinic acetylcholine receptor affinities, which may contribute to the clinical efficacy of clozapine and account for the correlation between NDMC/clozapine ratio and treatment response. Administration of NMDC reversed a striking hyperactive phenotype in the phospholipase C-[beta]1 knockout mouse, whereas no significant effects were observed in wild-type animals. This highlights the potential role of muscarinic activity in the behavioural response to NDMC. The M1 muscarinic antagonist pirenzepine, however, also reduced the hyperactive phenotype of these mice, emphasizing the importance of muscarinic function in the control of locomotor behaviour, but also calling into question the specific mechanism of action of NMDC at muscarinic receptors.
Language eng
DOI 10.1097/FBP.0b013e32830c3669
Field of Research 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2008, Lippincott Williams & Wilkins
Persistent URL http://hdl.handle.net/10536/DRO/DU:30075522

Document type: Journal Article
Collection: School of Medicine
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