Effects of asenapine, olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat.
Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and alpha(2)-adrenergic than dopaminergic D(2) receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats. After operant training, rats were treated acutely with d-amphetamine (0.75 mgkg intraperitoneally i.p.) or phencyclidine (PCP 1.5mgkg i.p.) or subchronically with PCP (2mgkg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute d-amphetamine- and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP. Deficits in reversal learning induced by acute d-amphetamine were attenuated by risperidone (0.2mgkg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mgkg subcutaneously s.c.), risperidone (0.2mgkg i.p.), and olanzapine (1.0mgkg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mgkg s.c.) and by olanzapine (1.5mgkg i.p.). Asenapine (0.075 mgkg s.c.), risperidone (0.2mgkg i.p.), and olanzapine (1.0mgkg i.p.) all showed sustained efficacy with chronic (29 days) treatment to improve subchronic PCP-induced impairments. These data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation.