Evaluation of the antipsychotic effect of bi-acetylated l-stepholidine (l-SPD-A), a novel dopamine and serotonin receptor dual ligand

Bi-acetylated l-stepholidine (l-SPD-A), a novel derivate of l-stepholidine (l-SPD), possesses a pharmacological profile of D1/5-HT1A agonism and D2 antagonism. In the present study, we examined the potential antipsychotic effect of l-SPD-A in a phencyclidine (PCP)-induced rat model of schizophrenia. Pretreatment with l-SPD-A blocked acute PCP-induced hyperlocomotion and reversed prepulse inhibition (PPI) deficits. Chronic l-SPD-A administration (i.p., 10 mg/kg/day for 14 days) improved social interaction and novel object recognition impairments in rats that were pretreated with PCP (i.p., 5 mg/kg/day for 14 days). Moreover, in a conditioned avoidance response (CAR) test, l-SPD-A, with either i.p. or oral administration, significantly decreased active avoidance without affecting the escape response of rats. Importantly, compared to that of the parent compound l-SPD, l-SPD-A showed stronger suppression of CARs. Lastly, using a [35S]GTPγS binding assay, we demonstrated that l-SPD-A improved impaired dopamine D1 receptor function in the prefrontal cortex (PFC) in chronic PCP-treated rats. Taken together, these results indicate that l-SPD-A was not only effective against the hyperactivity, but also improved the sensorimotor gating deficit, social withdrawal and cognitive impairment in an animal model of schizophrenia. The present data suggest that l-SPD-A, a potential neurotransmitter stabilizer, is a promising novel candidate drug for the treatment of schizophrenia.