Modulation of prepulse inhibition through both M(1) and M (4) muscarinic receptors in mice.

Rationale: Muscarinic cholinergic M(1) and M(4) receptors may participate in schizophrenia's etiology and have been proposed as targets for antipsychotic medications.

Objective: Here, we investigated the involvement of these receptors in behavioral measures pertinent to schizophrenia using knockout mice lacking M(1) receptors (M(1)-/-), M(4) receptors (M(4)-/-), or both (M(1)-/-M(4)-/-).

Methods: 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).

Results: In female (but not male) mice, combined deletion of both M(1) and M(4) receptors decreased PPI relative to wild-type mice, while knockout of either receptor alone had no significant effect. Scopolamine disrupted PPI in wild-type and M(4)-/- mice, but not in female M(1)-/-M(4)-/- or female M(1)-/- mice. When administered before scopolamine, xanomeline restored PPI in wild-type mice and M(1)-/- mice, but not in M(4)-/- mice. In contrast, pretreatment with oxotremorine increased PPI regardless of genotype. Effects of clozapine and haloperidol on PPI were not hindered by either mutation.

Conclusions: Deletion of both M(1) and M(4) receptors can disrupt PPI, suggesting that (at least partially redundant) M(1) and M(4) receptor-dependent functions are involved in sensorimotor gating mechanisms. PPI-disrupting effects of muscarinic antagonists appeared dependent upon M(1) receptor blockade. Our data also suggest that xanomeline exerts antipsychotic-like effects mainly through M(4) receptor stimulation, while stimulation of non-M(1)/M(4) subtypes may also have antipsychotic potential. Finally, our results do not support a role of M(1)/M(4) receptors in mediating antipsychotic-like effects of clozapine.