title: Role of muscarinic receptors in the activity of N-desmethylclozapine: reversal of hyperactivity in the phospholipase C knockout mouse.
abstract: Activity of the cholinergic muscarinic system is associated with modulation of locomotor activity, although the precise mechanism remains unclear. The phospholipase C-beta1 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-beta1 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.
authors.affiliation: Howard Florey Institute, University of Melbourne, Victoria, Australia. laura.gray@gms.edu.sg
authors.forename: Laura
authors.initials: L
authors.lastname: Gray
authors.forename: Caitlin
authors.initials: C
authors.lastname: McOmish
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scarr
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
mesh_terms: D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010641:Phenotype; D054799:Phospholipase C beta / Q000235:genetics*; D010890:Pirenzepine / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000187:drug effects*
chemical_list: D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; C058272:norclozapine; D010890:Pirenzepine; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse; D003024:Clozapine