Long-lasting sensitization induced by repeated risperidone treatment in adolescent Sprague-Dawley rats: a possible D2 receptor mediated phenomenon?

Risperidone use in children and adolescents for the treatment of various neuropsychiatric disorders (e.g., schizophrenia, autism, disruptive behavior, etc.) has increased substantially in recent decades. However, its long-term effect on the brain and behavioral functions is not well understood. The present study investigated how a short-term risperidone treatment in adolescence impacts antipsychotic response in adulthood in the conditioned avoidance response and phencyclidine (PCP)-induced hyperlocomotion tests. Male adolescent Sprague-Dawley rats (postnatal days [P] 40-44 or 43-48) were first treated with risperidone (0.3, 0.5, or 1.0 mg/kg, subcutaneously (sc)) and tested in the conditioned avoidance or PCP (3.2 mg/kg, sc)-induced hyperlocomotion model daily for five consecutive days. After they became adults (similar to P 76-80), they were challenged with risperidone (0.3 mg/kg, sc) to assess their sensitivity to risperidone reexposure. A quinpirole (a D-2/3 receptor agonist, 1.0 mg/kg, sc)-induced hyperlocomotion test was later conducted to assess the risperidone-induced functional changes in D-2 receptor. In the risperidone challenge test in adulthood, adult rats previously treated with risperidone in adolescence made significantly fewer avoidance responses and exhibited significantly lower PCP-induced hyperlocomotion than those previously treated with vehicle. They also appeared to be more hyperactive than the vehicle-pretreated ones in the quinpirole-induced hyperlocomotion test. Prepulse inhibition of acoustic startle or fear-induced 22 kHz ultrasonic vocalizations in adulthood was not altered by adolescence risperidone treatment. Adolescent risperidone exposure induces a long-term increase in behavioral sensitivity to risperidone that persists into adulthood. This long-lasting change might be due to functional upregulation of D-2-mediated neurotransmission.