The muscarinic M1/M4receptor agonist xanomeline exhibits antipsychotic-like activity in cebus apella monkeys

Abstract

Xanomeline is a muscarinic M1/M4preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducingextrapyramidalside effects (EPS) at therapeutically relevant doses. In the present study, we examined whetherthexanomeline-inducedfunctionaldopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whetherthe lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behaviorinduced byD-amphetamine and (—)-apomorphine in drug-naiveCebusapellamonkeys. Antipsychotic compounds antagonizeamphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibitedD-amphetamine-induced motor unrest, stereotypies and arousalaswellasapomorphine-induced stereotypies and arousal in drug-naiveCebusapellamonkeys. Xanomeline didnot induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patientsfollowing xanomeline administration. Even when xanomeline was tested in EPS-sensitizedCebusapellamonkeys, EPS were not observedat the dose range of xanomeline used in theD-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, whenxanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibitsd-amphetamine- and (—)-apomorphine-induced behavior inCebusapellamonkeys at doses that do not cause EPS. These data furthersubstantiate that muscarinic receptor agonists may be usefulin the pharmacologicaltreatment of psychosis. © 2003 Nature Publishing Group.