Catalepsy is Attenuated in Mutant Mice Lacking M4 Muscarinic Acetylcholine Receptors in D1 Dopamine Receptor-Expressing Cells

Abstract

An imbalance between striatal dopaminergic and muscarinic cholinergic pathways may be involved in the motor dysfunctions observed in Parkinson’s Disease patients and in patients treated with antipsychotic drugs. Muscarinic acetylcholine receptor (mAChR) antagonists alleviate motor symptoms in Parkinson's Disease patients as well as motor side effects induced by antipsychotic drugs. Among the five mAChR subtypes (M₁-M₅), the M₄ mAChR is abundantly expressed in the striatum, where it is preferentially localized in striatal projection neurons expressing D1 dopamine receptors. At the cellular level, stimulation of D1 and M₄ receptors exerts opposing effects on the activity of adenylyl cyclase (stimulation versus inhibition, respectively). To examine the functional importance of the M₄ mAChRs expressed by D1 dopamine receptor-expressing neurons, we employed Cre/loxP technology to generate mutant mice that lack M₄ mAChRs only in D1 dopamine receptor-expressing neurons (D1-M₄-KO mice). In rodents and nonhuman primates, antipsychotics may induce a characteristic motor response referred to as catalepsy, which is predictive of the severity of motor side effects in patients. In the present study, we investigated the potential role of M₄ mAChRs in catalepsy induced by the antipsychotic drugs, haloperidol and risperidone and its inhibition by scopolamine, a mAChR antagonist. We found that the cataleptic response to haloperidol (0.3 and 1.0 mg/kg) and risperidone (1.0 and 3.0 mg/kg) in D1-M₄-KO mice was attenuated. The catalepsy could be reversed by scopolamine. These results indicate an important role of muscarinic cholinergic M₄ receptors in the pathophysiology of Parkinsonian symptoms induced by antipsychotics as well as in Parkinson's Disease.