Loss of anti-cataleptic effect of scopolamine in mice lacking muscarinic acetylcholine receptor subtype 4.

Motor dysfunction associated with dyskinesia can be caused by imbalance between dopaminergic and cholinergic actions. Antimuscarinic agents are used to treat extrapyramidal symptoms in Parkinson's disease and extrapyramidal side effects of antipsychotics. These therapeutic effects are mediated by blockade of the striatal muscarinic receptors, which comprise five distinct subtypes (M(1-5)). To evaluate the role of muscarinic M(4) receptors, we have generated mutant mice lacking this subtype (muscarinic M(4) receptor-knockout mice) and analyzed their cataleptic responses induced by haloperidol (an animal model of extrapyramidal side effects). While the muscarinic M(4) receptor-knockout mice developed the cataleptic response normally, systemic administration of scopolamine could not suppress the cataleptic response. These results suggest that acute, but not chronic, blockade of muscarinic M(4) receptors plays important roles in the therapeutic effects of antimuscarinic agents.