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Vol. 299, Issue 2, 782-792, November 2001
Vernalis Research Limited, Winnersh, Wokingham, United Kingdom
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.
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