Gray Laura, McOmish Caitlin, Scarr Elizabeth, Dean Brian, Hannan Anthony J
Howard Florey Institute, University of Melbourne, Victoria, Australia.
Behav Pharmacol. 2008 Sep;19(5-6):543-7. doi: 10.1097/FBP.0b013e32830c3669.
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.
胆碱能毒蕈碱系统的活性与运动活动的调节有关，尽管其确切机制尚不清楚。磷脂酶C-β1基因敲除小鼠表现出M1毒蕈碱受体功能障碍和运动亢进表型。该小鼠是分析毒蕈碱对运动活动调节的理想模型。氯氮平代谢物N-去甲基氯氮平（NDMC）已显示出作为精神病性障碍替代或辅助治疗的一些前景。NDMC表现出很强的毒蕈碱型乙酰胆碱受体亲和力，这可能有助于氯氮平的临床疗效，并解释了NDMC/氯氮平比值与治疗反应之间的相关性。给予NMDC可逆转磷脂酶C-β1基因敲除小鼠显著的运动亢进表型，而在野生型动物中未观察到明显影响。这突出了毒蕈碱活性在对NDMC行为反应中的潜在作用。然而，M1毒蕈碱拮抗剂哌仑西平也降低了这些小鼠的运动亢进表型，这强调了毒蕈碱功能在控制运动行为中的重要性，但也对NMDC在毒蕈碱受体上的具体作用机制提出了质疑。
