Psychology, Department of


Date of this Version



Published in final edited form as: Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 177–185; doi: 10.1016/j.pnpbp.2013.10.005


Copyright © 2013 Elsevier Inc. Used by permission. (The PubMed Central version is archived here, in accord with Elsevier policy.)


This preclinical study investigated howa short-termrisperidone treatment in adolescence impacts antipsychotic response to olanzapine and clozapine in adulthood. Antipsychotic effect was indexed by a drug's suppressive effect on avoidance responding in a rat conditioned avoidance response (CAR) model. Male adolescent Sprague–Dawley rats were first treated with risperidone (1.0mg/kg, sc) or sterile water and tested in the CAR model for 5 consecutive days from postnatal days P 40 to 44. After they became adults (~P 80–84), they were switched to olanzapine (0.5mg/kg, sc), clozapine (5.0mg/kg, sc) or vehicle treatment and tested for avoidance for 5 days. During the adolescent period, repeated risperidone treatment produced a persistent inhibition of avoidance response. Throughout the 5 days of adulthood drug testing, rats previously treated with risperidone in adolescencemade significantly fewer avoidance responses than the vehicle oneswhen they all were switched to olanzapine, indicating a risperidone-induced enhancement of behavioral sensitivity to olanzapine. In contrast, when switched to clozapine, rats previously treated with risperidone made significantly more avoidance responses than the vehicle rats, indicating a risperidone-induced decrease of behavioral sensitivity to clozapine. Performance in the prepulse inhibition of acoustic startle response in adulthood was not altered by adolescent risperidone treatment. Collectively, adolescent risperidone exposure induced a long-term change in behavioral sensitivity to other atypical antipsychotic drugs, with the specific direction of change (i.e., increase or decrease) dependent on the drug to be switched to. These long-lasting changes are likely mediated by drug-induced neuroplastic changes and may also have significant clinical implications for antipsychotic treatment of chronic patients with an early onset of psychotic symptoms.