Research reportTime-dependence of risperidone and asenapine sensitization and associated D2 receptor mechanism

•Repeated risperidone and asenapine treatment enhanced acute effect of these drugs in the conditioned avoidance model.•Risperidone and asenapine sensitization lasted up to 40 days.•Risperidone and asenapine sensitization increased with the passage of time.•Repeated risperidone treatment caused a functional upregulation of dopamine D2/3 receptors.

When an antipsychotic drug is given repeatedly and intermittently, there is often a long-term increase in its behavioral efficacy, termed antipsychotic sensitization. With the passage of time, the magnitude of antipsychotic sensitization may increase or decrease based on the principle of time-dependent sensitization (TDS) or memory decay, respectively. In the present study, we examined the time-dependent feature and possible dopamine D2 receptor mechanism of sensitization induced by risperidone and asenapine in the conditioned avoidance response test. Well-trained male adult Sprague-Dawley rats were first repeatedly treated with risperidone (1.0 mg/kg) or asenapine (0.2 mg/kg) and tested for avoidance response daily for 5 consecutive days. Eight, 18 or 38 days after the 5th drug treatment, all rats were retested drug-free to assess the long-term impact of prior risperidone or asenapine treatment. Drug-pretreated rats had significantly lower avoidance than vehicle-pretreated ones on this test, and the group differences increased with the passage of time. In the subsequent drug challenge test at 10, 20 or 40 days after the 5th drug treatment, all rats were injected with a low dose of risperidone (0.3 mg/kg) or asenapine (0.1 mg/kg). Drug-pretreated rats again made significantly fewer avoidances than controls, confirming the antipsychotic sensitization effect. Finally, in the quinpirole (a D2/3 receptor agonist, 1.0 mg/kg, sc)-induced hyperlocomotion test, risperidone-pretreated rats exhibited a significantly higher level of motor activity than the vehicle-pretreated ones. These findings suggest that risperidone and asenapine sensitization is long-lasting, follows the TDS principle, and is likely mediated by D2 receptor supersensitivity.