PT-31, a putative α2-adrenoceptor agonist, is effective in schizophrenia cognitive symptoms in mice

Abstract

Evidence of changes in central noradrenergic activity has been reported in schizophrenic patients and studies indicate that activation of the α2-adrenoceptor improves memory and neuroprotection. In this study, a new imidazolidine derivative 3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione, PT-31, a putative α2A-adrenoceptor agonist, was evaluated in mouse models predictive of efficacy in the treatment of positive and cognitive symptoms of schizophrenia, as well as its ability to promote cerebellar granule cell survival in vitro, in the presence or absence of glutamate (100 µmol/l). PT-31 prevented apomorphine-induced climbing and the ketamine-induced hyperlocomotion, without inducing catalepsy or motor impairment. PT-31 protected against the impairment of prepulse inhibition induced by apomorphine, (±)-DOI, and ketamine. The molecule did not affect mouse short nor long-term memory per se, but it protected against ketamine-induced memory impairment when administered at different stages of the memory process (acquisition, consolidation, and retrieval) in the novel object recognition task. When added to cultured cerebellar granule neurons, PT-31 was not toxic per se and protected neurons from glutamate-induced apoptosis. In conclusion, PT-31 displayed a preclinical pharmacology predictive of neuroprotective effects and efficacy in relieving schizophrenia symptoms, without inducing motor side effects, suggesting that it could represent a molecular scaffold for antipsychotic drug development.