| Adolescence is the time when symptoms of many severe mental disorders often manifest. In clinical practice, antipsychotic drugs (APDs) are the primary medications used to treat psychosis. As antipsychotic treatment has seen a dramatic increase in recent decades in children and adolescents, and among those who are treated with APDs, the majority is on atypical drugs, there is a crucial need to evaluate the possible short-term and long-term impacts of atypical antipsychotic medications in adolescence on psychological functions and drug response. Like many other psychoactive drugs, repeated administration of APDs often induces various clinically relevant behavioral sensitization and tolerance effects. And antipsychotic sensitization and tolerance are relatively newly recognized phenomena in adult animals. Using conditioned avoidance response (CAR) test, a rodent model with high predictive validity for antipsychotic efficacy, researchers showed that in adult rats repeated administration of atypical antipsychotics could induce two different behavioral patterns in challenge test (e.g.. olanzapine sensitization and clozapine tolerance). In this model, antipsychotic effect was indexed by a drug’s selective suppression of conditioned avoidance responding because the ability of an APD to inhibit CAR has been shown to be closely correlated with its clinical potency. Based on these findings, the present thesis proposed (1) the short-term behavioral effects of repeated atypical antipsychotic treatment in adolescent rats, (2) the long-term behaviora effects of repeated atypical antipsychotic treatment during adolescence, and (3) the generalization profile for the long-term effects induced by repeated atypical antipsychotic treatment in adolescent rats.In the first study, we performed two experiments to examine whether olanzapine (OLZ) sensitization and clozapine (CLZ) tolerance could be induced in adolescent rats in the CAR model as previously found in adult rats. Male adolescent Sprague-Dawley rats (approximate postnatal days (～P) 43-47) were first repeatedly treated with OLZ (1.0 or 2.0 mg/kg, subcutaneously (sc)) or CLZ (10 or 20 mg/kg, sc) in the CAR model for 5 consecutive days. They were then evaluated for the expression of OLZ sensitization or CLZ tolerance in adolescence (～P 50) in a challenge test during which all rats were injected with either a lower dose of OLZ (0.5 mg/kg, sc) or CLZ (5.0 mg/kg, sc). The results showed that rats previously treated with OLZ made a stronger inhibition of CAR than those previously treated with vehicle (ie, sensitization), whereas rats with pretreatment of CLZ made a weaker inhibition of CAR than those with pretreatment of vehicle (ie, tolerance). Performance in fear-induced 22 kHz ultrasonic vocalizations in adolescence was not altered by drug treatment. Results from these two experiments suggest that repeated atypical antipsychotic treatment during adolescence can induce a short-term alteration in antipsychotic effect.In the second study, we used an altered paradiam in the CAR model to investigate the extent to which olanzapine sensitization and clozapine tolerance induced in adolescence persists into adulthood. Male adolescent SD rats (～P 43-47) were first treated with the same drug dose and schedule as which were used in study 1. They were then tested for the expression of OLZ sensitization or CLZ tolerance after they matured into adults (～P 76 and 92) in a challenge test with OLZ (0.5 mg/kg, sc) or CLZ (5.0 mg/kg, sc), respectively. The results showed that the OLZ sensitization was still detectable at both time points (～P 76 and 92) when tested in adulthood. In contrast, the CLZ tolerance was only found on ～P 76, and only manifested in the intertrial crossing. Performance in the prepulse inhibition and fear-induced 22 kHz ultrasonic vocalizations in adulthood were not altered by adolescence drug treatment. These findings provide direct evidence for a long-term specific alteration in antipsychotic effect by repeated atypical antipsychotic treatment during adolescence.In the third study, we addressed how a short-term risperidone treatment in adolescence impacted antipsychotic response to risperidone, olanzapine and clozapine in adulthood.In experiment 5, male adolescent SD rats (～P 40-44) were first treated with risperidone (RIS) (0.5 or 1.0 mg/kg, sc) daily for five consecutive days in the CAR model. After they became adults (～P 80), they were all challenged with RIS (0.3 mg/kg, sc) to assess their sensitivity to risperidone reexposure. We found that adult rats previonsly Seated with RIS in adolescence exhibited significantly fewer avoidance responses than those previously treated with vehicle (ie, sensitization). Building on the evidence of a long-term increase in behavioral sensitivity to risperidone, we then conducted experiment 6 to investigate how a short-term risperidone treatment in adolescence impacts antipsychotic response to olanzapine and clozapine in adulthood. Male adolescent SD rats (～P 40-44) were first treated with RIS (1.0 mg/kg, sc) or sterile water and tested in the CAR model for 5 consecutive days. After they became adults (-P 80-84), they were switched to OLZ (0.5 mg/kg, sc), CLZ (5.0 mg/kg, sc) or vehicle treatment and tested for 5 days. Rats with adolescent RIS treatment showed significantly stronger inhibition of CAR than the vehicle ones when they all were switched to OLZ, indicating a RIS-induced enhancement of behavioral sensitivity to OLZ. In contrast, when switched to CLZ, rats with adolescent RIS treatment showed significantly more avoidance responses than the vehicle rats, indicating a RIS-induced decrease of behavioral sensitivity to CLZ. Performance in the prepulse inhibition of acoustic startle and fear-induced 22 kHz ultrasonic vocalizations were also tested in study 3 and there was no change in adulthood by adolescence RIS treatment. These findings suggest such a long-term alteration of behavioral sensitivity induced by repeated atypical antipsychotic treatment in adolescence is a general phenomenon and can be transferred from one drug to another.Collectively, these findings suggest that repeated atypical antipsychotic treatment during adolescence can induce a long-term specific alteration in antipsychotic effect that persists into adulthood despite the brain maturation and such a long-term alteration is a general effect among atypical antipsychotics. |
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