Repeated administration of 5‐hydroxytryptamine 2C agonist MK212 produces a sensitization effect of antipsychotic activity

5‐Hydroxytryptamine 2C (5‐HT 2C ) receptor agonists have been suggested to possess an antipsychotic activity in several acute preclinical tests of antipsychotic drugs with low extra‐pyramidal side effect liability. However, little is known about the long‐term effect associated with chronic use of 5‐HT 2C receptor agonists. The present study examined whether repeated activation of 5‐HT 2C receptor with a highly selective 5‐HT 2C receptor agonist MK212 would induce a long‐term change in its antipsychotic‐like activity (either a sensitization or tolerance) in the conditioned avoidance response and MK801‐induced hyperlocomotion tests. Sprague‐Dawley rats were first tested under the intraperitoneal (i.p.) treatment of MK212 (0.25, 0.5, 1.0 mg/kg) for 5 consecutive days. Three days later, when all rats were injected with a low dose of MK 212 (0.25 mg/kg) and tested for avoidance responding, rats that had been pretreated with 1.0 and 0.5 mg/kg MK212 made significantly fewer avoidance responses than those that had been treated with vehicle (0.9% saline). However, this past drug exposure‐induced group difference was not significant in the MK801‐induced hyperlocomotion test. Overall, results from this study suggest that repeated treatment of MK212 is capable of inducing a dose‐dependent sensitization of antipsychotic activity in conditioned avoidance response. The discrepancy in sensitization of MK212 in CAR and MK801‐induce hyperlocomotion may be related to the different mechanism underlying the effect of MK212 in these two tests. © 2016 IUBMB Life, 68(12):985–993, 2016