The muscarinic receptor agonist xanomeline has an anti psychotic-like profile in the rat

The muscarinic receptor agonist xanomeline was examined and compared with t he antipsychotics clozapine and/or haloperidol in the following in vivo rat models: apomorphine-induced disruption of prepulse inhibition (PPI), amphe tamine-induced hyperlocomotion, and the conditioned emotional response (CER ) test. The effects of xanomeline were also assessed ex vivo on dopamine tu rnover in the rat medial prefrontal cortex. Under conditions of varying dos e and prepulse intensity, xanomeline, like haloperidol, had no effect on PP I. In contrast, the muscarinic receptor antagonist scopolamine and the musc arinic receptor agonist pilocarpine both induced significant dose-dependent deficits in PPI. Haloperidol and xanomeline, but not pilocarpine, dose dep endently reversed apomorphine-induced disruption of PPI. Thus, xanomeline i nduced a clear anti psychotic-like effect in PPI, whereas pilocarpine appea red to induce a psychotomimetic-like effect. Xanomeline attenuated amphetam ine-induced hyperactivity at doses that had no effect on spontaneous activi ty, possibly indicating a separation between attenuation of limbic hyperdop aminergic function and the induction of hypolocomotion. Haloperidol and clo zapine also reversed amphetamine-induced hyperlocomotion, but at similar do ses to those that reduced spontaneous locomotion. Clozapine, but not halope ridol had an anxiolytic-like effect in the CER test. The effects of xanomel ine in the CER test were similar to those of clozapine, although at the anx iolytic dose it tended to disrupt baseline levels of lever pressing. Finall y, haloperidol, clozapine, pilocarpine, and xanomeline, all induced an incr ease in dopamine turnover in medial prefrontal cortex. The antipsychotic-li ke effects of xanomeline in the animal models used here suggest that it may be a useful treatment for psychosis.