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Muscarinic cholinergic M₁ and M₄ receptors may participate in schizophrenia’s etiology and have been proposed as targets for antipsychotic medications.

Here, we investigated the involvement of these receptors in behavioral measures pertinent to schizophrenia using knockout mice lacking M₁ receptors (M₁−/−), M₄ receptors (M₄−/−), or both (M₁−/−M₄−/−).

We measured prepulse inhibition (PPI) of startle without drugs and after treatment with scopolamine (0.32–1.8 mg/kg), xanomeline (3.2 mg/kg), oxotremorine (0.032–0.1 mg/kg), clozapine (1.0–5.6 mg/kg), or haloperidol (0.32–3.2 mg/kg).

In female (but not male) mice, combined deletion of both M₁ and M₄ receptors decreased PPI relative to wild-type mice, while knockout of either receptor alone …