The
muscarinic receptor agonist
xanomeline was examined and compared with the
antipsychotics clozapine and/or
haloperidol in the following in vivo rat models:
apomorphine-induced disruption of prepulse inhibition (PPI),
amphetamine-induced hyperlocomotion, and the conditioned emotional response (CER) test. The effects of
xanomeline were also assessed ex vivo on
dopamine turnover in the rat medial prefrontal cortex. Under conditions of varying dose and prepulse intensity,
xanomeline, like
haloperidol, had no effect on PPI. In contrast, the
muscarinic receptor antagonist
scopolamine and the
muscarinic receptor agonist
pilocarpine both induced significant dose-dependent deficits in PPI.
Haloperidol and
xanomeline, but not
pilocarpine, dose dependently reversed
apomorphine-induced disruption of PPI. Thus,
xanomeline induced a clear
antipsychotic-like effect in PPI, whereas
pilocarpine appeared to induce a psychotomimetic-like effect.
Xanomeline attenuated
amphetamine-induced hyperactivity at doses that had no effect on spontaneous activity, possibly indicating a separation between attenuation of limbic hyperdopaminergic function and the induction of hypolocomotion.
Haloperidol and
clozapine also reversed
amphetamine-induced hyperlocomotion, but at similar doses to those that reduced spontaneous locomotion.
Clozapine, but not
haloperidol had an
anxiolytic-like effect in the CER test. The effects of
xanomeline in the CER test were similar to those of
clozapine, although at the
anxiolytic dose it tended to disrupt baseline levels of lever pressing. Finally,
haloperidol,
clozapine,
pilocarpine, and
xanomeline, all induced an increase in
dopamine turnover in medial prefrontal cortex. The
antipsychotic-like effects of
xanomeline in the animal models used here suggest that it may be a useful treatment for
psychosis.