Time-dependent Sensitization Of Antipsychotic Effect In Adolescent Rats

Many behavioral and biological effects of a psychoactive drug often undergo time-dependent change in its strength following even one single drug exposure.AIM:The present study examined whether one or two exposures of haloperidol,olanzapine or clozapine would also induce a time-dependent change in their behavioral effects in adolescent rats and whether such a change vary between sexes.METHODS:Adolescent Sprague-Dawley male and female rats(<40 days old)were first treated with one single injection of haloperidol(0.05 and 0.1 mg/kg,sc),clozapine(10 and 20 mg/kg,sc),2 injections of olanzapine(1 and 2 mg/kg,sc)or vehicle,and tested in a conditioned avoidance response(CAR)model or a PCP(3.20 mg/kg,sc)-induced hyperlocomotion model to assess their antipsychotic-like behavioral effects.One or three weeks later,rats were challenged with one of the drugs(haloperidol 0.03 mg/kg,clozapine 5 mg/kg,olanzapine 0.5 mg/kg,sc)and their avoidance responses and the PCP-induced hyperlocomotion were re-assessed.RESULTS:Consistent with previous reports,one-trial of haloperidol,clozapine and 2-trial olanzapine suppressed the conditioned avoidance response or PCP-induced hyperlocomotion.At the challenge tests,rats that were previously treated with haloperidol and olanzapine exhibited an enhanced suppression of these behaviors(a sensitization effect),while those treated with clozapine exhibited a decreased suppression(a tolerance effect).More importantly,when the magnitude of the sensitization and tolerance were compared,haloperidol sensitization found in the PCP model was significantly higher at the 3-week time point than at 1-week point,especially in the females.Clozapine tolerance in the conditioned avoidance response model also exhibited the time-dependent change in both sex groups,with the males showing a statistically significant time-dependent decrease.Olanzapine sensitization in both models did not show a significant change over time.CONCULSIONS:Overall,the time-dependent sensitization and tolerance can be demonstrated in antipsychotic drugs under certain conditions and females appear to be more responsive to the effect.Many pharmacological(e.g.specific drugs,drug doses),individual(e.g.male versus female)and environmental(e.g.specific behavioral models)factors all play a role in the modulation of the strength of antipsychotic sensitization and tolerance.Time-dependent effect of HAL sensitization induced by one-trial HAL treatment in the PCP-induced hyperlocomotion modelThis experiment examined the effect of time interval between initial one-trial drug exposure(the induction phase)and subsequent drug challenge(the expression phase)on the strength of HAL sensitization in PCP-induced hyperlocomotion model.The entire experiment was comprised of the two phases:one-trial HAL test phase(the induction phase)and the challenge test phase(the expression phase).Table 1 details the timeline of events.In the induction phase,72 adolescent rats were randomly assigned to 1 of 3 groups:VEH +PCP(male:n = 12;female n = 12),HAL 0.05 + PCP(HAL 0.05 mg/kg,male:n = 12;female:n=12),HAL 0.1 + PCP(HAL 0.1 mg/kg,male:n = 12;female:n = 12).All rats(approximately PND 32)were first handled and habituated to the locomotor activity apparatus for 2 days(30 min/day).On the next day,they were first injected with VEH(saline),HAL 0.05 or 0.1 mg/kg and then immediately placed in the locomotor activity boxes for 30 min.At the end of the 30-min period,they were taken out and injected with PCP(3.2 mg/kg,sc)and placed back in the boxes for another 60 min.Locomotor activity(number of photobeam breaks)was measured in 5 min intervals throughout the entire 90-min testing session.After the initial HAL test,each group was split into two subgroups(n = 6/subgroup),with one subgroup being challenged with HAL(0.03 mg/kg,sc)at 1 week after the initial HAL test and other subgroup at 3 weeks after.Specifically,6 or 20 days after the initial HAL test,rats were returned to the locomotor activity boxes for re-habituation session(30 min),followed by the HAL challenge test one day later.On the challenge day,rats were first injected with HAL 0.03 mg/kg and then immediately placed into the locomotor activity boxes for 30 min.At the end of the 30-min period,they were taken out and injected with PCP and placed back in the boxes for another 60 min.Time-dependent effect of CLZ tolerance induced by one-trial CLZ treatment in the PCP-induced hyperlocomotion model and in the CAR modelPCP Model:This experiment examined the effect of time interval between the initial one-trial CLZ exposure and subsequent drug challenge on the strength of CLZ tolerance in the PCP-induced hyperlocomotion model.The basic procedure was identical to that used in Experiment 1(Table 1).Seventy-two rats were used and assigned into 3 groups:VEH + PCP(male:n = 12;female n = 12),CLZ 10.0 + PCP(CLZ 10.0 mg/kg,male:n = 12;female:n = 12),CLZ 20.0 + PCP(CLZ 20.0 mg/kg,male:n = 12;female:n = 12).They were then split into 6 subgroups after the initial CLZ test,and challenged with CLZ(5.0 mg/kg,sc)at either 1 week or 3 weeks after.CAR Model:In this experiment,we further examined the time-dependent tolerance effect of CLZ treatment using the another well validated animal behavioral test of antipsychotic activity:the conditioned avoidance response(CAR)model.Forty-eight adolescent male and female rats were first habituated to the CAR boxes for 2 days(PND 31 and 32,30 min/day)and then trained for conditioned avoidances responding for 7 consecutive days/sessions(PND 33-39,CS-US).The total number of avoidance responses was recorded for each session.At the end of the training session,they acquired a robust avoidance responding(?70%avoidance in each of the last 2 session),and were assigned to 1 of 2 groups:VEH(1.0-1.5%glacial acetic acid in distilled sterile water,male:n = 12;female:n = 12),or CLZ(clozapine 20 mg/kg,male:n = 12;female:n=12).On PND 40,all rats were tested for avoidance responding under the CS-only condition(no shock,30 trials/session)1 h later after the CLZ injection.One week after the CLZ test,half of rats from each group were returned to the CAR boxes for 2 days of CAR retraining(PND 48 and 49,CS-only and CS-US,30 trials/session),then challenged with CLZ(5.0 mg/kg,sc)one day later(the challenge day,PND 50).They were tested for avoidance response in the CS-only condition(30 trials)1 h after the CLZ injection.The remaining rats were tested for CLZ tolerance 3 weeks after the initial CLZ test(PND 67).Table 2 details the timeline of events.Time-dependent effect of OLZ sensitization induced by two-trial OLZ treatment in the PCP-induced hyperlocomotion model and in the CAR modelPCP Model:This experiment examined the time-dependent effect of OLZ sensitization using the PCP-induced hyperlocomotion model.The basic procedure was identical to that of Experiment 1 and 2(Table 1).In the induction phase,we gave two OLZ injections instead of one because the 1st injection of OLZ did not cause an apparent suppression of the PCP-induced hyperlocomotion.In this experiment,72 adolescent female and male rats were used,and were assigned to 1 of 3 groups:VEH + PCP(male:n = 12;female:n = 12),OLZ 1.0 + PCP(OLZ 1.0 mg/kg,male:n = 12;female:n = 12)and OLZ 2.0 + PCP(OLZ 2.0 mg/kg,male:n = 12;female:n = 12).Again,the challenge tests were conducted at 1 week or 3 weeks after the last OLZ treatment with a challenge dose of OLZ(0.5 mg/kg,sc).CAR Model:This experiment was identical to that of Experiment 3,except that rats were injected with OLZ two times in the induction phase.Table 2 details the timeline of events.