Antipsychotic-induced catalepsy is attenuated in mice lacking the M4 muscarinic acetylcholine receptor

Abstract

A delicate balance exists between the central dopaminergic and cholinergic neurotransmitter systems with respect to motor function. An imbalance can result in motor dysfunction as observed in Parkinson's disease patients and in patients treated with antipsychotic compounds. Cholinergic receptor antagonists can alleviate extrapyramidal symptoms in Parkinson's disease and motor side effects induced by antipsychotics. The effects of anticholinergics are mediated by muscarinic receptors of which five subtypes (M1–M5) exist. Muscarinic M4 receptors are found at high concentrations in motor parts of the striatum, suggesting a role for muscarinic M4 receptors in the motor side effects of antipsychotics, and in the alleviation of these side effects by anticholinergics. Here we investigated the potential role of the muscarinic M4 receptor in catalepsy induced by antipsychotics (haloperidol and risperidone) as well as the anti-cataleptic effects of the non-selective anticholinergic drug scopolamine in fully backcrossed muscarinic M4 receptor knockout mice. The drug-induced catalepsy was strongly attenuated, but not abolished, in M4 knockout mice as compared to wild-type controls. Scopolamine further attenuated the cataleptic response in M4 knockout mice, suggesting that non-M4 muscarinic receptors also participate in the anti-cataleptic effects. In conclusion, these data indicate an important role for M4 receptors in antipsychotic-induced motor side effects and suggest that M4 receptors could be a target for future pharmacological treatment of antipsychotic-induced as well as idiopathic parkinsonism.