Asenapine improves phencyclidine-induced object recognition deficits in the rat: evidence for engagement of a dopamine D1 receptor mechanism

Cognitive deficits are common in schizophrenia. Asenapine is an atypical antipsychotic approved by the US Food and Drug Administration in adults for treatment of schizophrenia or acute treatment, as monotherapy or adjunct therapy to lithium or valproate, of manic or mixed episodes of bipolar I disorder. Based on the receptor pharmacology of asenapine, the current study assessed the efficacy and mechanism of action of asenapine to improve a subchronic phencyclidine (PCP)-induced deficit in visual recognition memory using the novel object recognition (NOR) paradigm in the rat, a paradigm of relevance to cognition in schizophrenia. Female-hooded Lister rats received vehicle or PCP (2 mg/kg, i.p.) for 7 days, followed by a 7-day washout. On the test day, rats were given asenapine (0.001-0.1 mg/kg, s.c.) alone or in combination with the D-1 receptor antagonist SCH-23390 (0.05 mg/kg, i.p.) or 5-HT1A receptor antagonist WAY100635 (1 mg/kg, i.p.). Time spent exploring two identical objects during a 3-min acquisition trial (followed by a 1-min intertrial interval) and then a familiar and a novel object for another 3 min (retention trial) were recorded onto videotape and scored blind. In the retention trial, vehicle- but not PCP-treated animals explored the novel object significantly more than the familiar object (p < 0.001). Asenapine (0.01-0.075 mg/kg) reversed PCP-induced deficits in NOR (p < 0.01-0.001) in a dose-related manner. This effect was antagonised by SCH-23390 but not by WAY100635. These results demonstrate a role for D-1 but not 5-HT1A receptor mechanisms in mediating the cognitive effects of asenapine in this rodent model.