Olanzapine이 백서의 Schedule-Induced Polydipsia에 미치는 영향

이기철,이경규,장환일,이정호,김현우,하준명,정재현,정홍경,Lee, Gi-Chul,Lee, Kyung-Kyu,Chang, Hwan-Il,Lee, Jung-Ho,Kim, Hyun-Woo,Ha, Jun-Myung,Jeong, Jae-Hyun,Jeong, Hong-Kyung 대한생물정신의학회 1999 생물정신의학 Vol.6 No.2

Object : This study was designed to evaluate the effects of olanzapine on the schedule-induced polydipsia(SIP) which is one of animal model of obsessive-compulsive disorder in rats. We administered olanzapine as a serotonin and dopamine blocking agent, fluoxetine as a selective serotonin reuptake inhibitor, and haloperidol for the dopamine antagonist to rats which showed schedule-induced polydipsic behavior. Methods : Spraque-Dawley rats weighing 200-250gm were individually housed and maintained and allowed free access to water. The rats were placed on a restricted diet. To induce polydipsia, rats were placed in the cage where a pellet dispenser automatically dispensed 90mg pellets on a fixed-time 60 seconds(FT-60s) feeding schedule over 150 minute test session per day. Water was available at all times in the cage. After 4 weeks of daily exposure to the FT 60s feeding schedule, experimental rats met a predetermined criterion for polydipsic behavior(greater than 3 times of water per session on average). 5 groups of rats were administered olanzapine(3mg/kg, i.p), olanzapine(10mg/kg, i.p), fluoxetine(5mg/kg, i.p.), haloperidol(0.1mg/kg, i.p.), and vehicle(1cc/kg, i.p.) for 3 weeks. The rats were tested once a week to access schedule induced polydipsic behavior. Water bottles were weighed before and after the 150-minute test session. The chronic effects of administration of experimental drugs on schedule induced polydipsic behavior were analyzed with ANOVA and Scheffe test as a posthoc comparison. In order to measure water consumption in non-polydipsic food-deprived rats, a separate group of rats(N=8) were individually housed and given a single bolus(14.5gm) of food per day which maintained them at their average body weight. Results and Conclusion : The results were as follows ; 1) After 4 weeks of scheduled feeding procedure, the experimental group showed significant differences than the bolus control in the amount of water consumption as compared with their average water intakes for 4 weeks. At the same periods, there were no differences between the experimental group and the bolus control in the body weight. 2) The fluoxetine group showed significant decrease in the amount of water intake over the 3 weeks of drug treatment as compared with their average amount of polydipsic water intakes. The olanzapine 3mg group showed significant decrease in the amount of water intake at 3rd weeks of drug treatment as compared with their average amount of polydipsic water intakes. The olanzapine 10mg group showed significant decrease in the amount of water intake at 2nd and 3rd weeks of drug treatment as compared with their average amount of polydipsic water intakes. However, the haloperidol group and the vehicle control group showed no changes of amounts of water intake for 3 weeks of treatment as compared with their average amount of polydipsic water intakes. 3) The fluoxetine group showed significantly lower amounts of water intake than the haloperidol group at 2nd weeks of drug treatment. And also the fluoxetine group showed significantly lower amounts of water intake than the haloperidol group and the vehicle control at 3rd weeks of drug treatment. The olanzapine 3mg group and the olanzapine 10mg group showed significantly lower amounts of water intake than the haloperidol group and the vehicle control at 3rd weeks of drug treatment. Above findings suggest that the fixed time feeding procedure for schedule-induced polydipsia as an animal model of obsessive compulsive disorder was effective to the evaluation of pharmacological challenge study. The authors assume that the serotonin hypothesis and the serotonin-dopamine interaction hypothesis are preferred to the dopamine hypothesis in the biological etiology of obsessive-compulsive disorder.

Risperidone이 백서의 Schedule-Induced Polydipsia에 미치는 영향

이기철,이정호,윤도준,최영민,전성일,김태수,정홍경,하준명,정재현 大韓神經精神醫學會 2000 신경정신의학 Vol.39 No.3

연구목적 : 강박장애의 원인론중 세로토닌-도파민 가설에 기초하여 강박장애 동물모형으로 고려되는 고정된 시간 간격으로 평소의 먹이섭취량보다 작은 양의 음식물을 백서에게 장기간 공급하여 다음중(schedule-induced polydipsia : SIP)을 유발시켰다. SIP모형에 강박장애에 효과적이라고 알려진 선택적 세로토닌 재흡수 차단제로서 fluoxetine을 장기 투여하고, 신경절후 5-HT²와 도파민 D² 수용체를 동시에 차단하는 risperidone을 투여하고, 신경절후 도파민 수용체 차단제인 haloperidol을 투여하였다. 그결과로서 risperidone이 강박장애 동물모형으로 고려되는 SIP에서 어떤 영향을 미치는지 알아보았다. 방 법 : SIP를 유발하기 위해 각각의 사육상자에 1정당 90㎎의 사료를 자동급이장치 (automatic dispenser)에서 60초당 1정씩 고정된 시간 간격으로 하루에 150분씩 공급하였다. 4주간 고정된 시간 간격으로 머기를 공급하고 매주 음수량과 체중을 측정한 실험 동물과 동등한 사료의 양을 한번에 덩어리로 공급받은 통제 집단의 체중과 음수량을 비교하였다. SIP 행동변화를 보인 실험 동물들을 fluoxetine 5㎎/㎏(N=8), risperidone 0.1㎎/㎏(N=8), haloperidol 0.1㎎/㎏(N=8), 그리고 vehicle 대조군 1㏄/㎏(N=8)으로 나누고 각각의 실험 동물군에서 3주간에 걸쳐서 실험 약물을 매일 복강내 주사하였다. 매주 실험 동물의 음수량과 체중을 측정, 비교하였다. 결 과 : 1) 고정된 시간 간격으로 제한된 먹이를 공급한 실험 동물군은 1주부터 4주에 걸쳐서 기저치보다 유의한 음수량의 증가를 보였다. 반면 통제 집단은 2주째 음수량이 일시적으로 증가한 소견 이외에 4주간의 실험 기간중 유의한 변화는 보이지 않았다. 실험 동물과 통제 집단간의 음수량에서 3주와 4주째에 실험 동물이 통제 집단보다 유의하게 높은 음수량을 보였지만 양군간에 체중의 차이는 보이지 않았다. 2) 각각의 실험 동물군 내에서 risperidone 0.1㎎ 투여군은 약물 투여 2주부터 3주까지 기저치 음수량과 비교하여 유의한 저하를 보였다. Risperidone 0.5㎎ 투여군은 약물터여 3주에서 기저치의 음수량과 비교하여 유의한 저하를 보였다. Fluoxetine 투여군은 약물 투여 시작 1주부터 3주에서 기저치의 음수량과 비교하여 유의한 저하를 보였다. 한편, haloperidol 투여군과, vehicle은 3주간에 걸친 약물 투여에서 각각의 기저치 음수량과 비교하여 차이를 보이지 않았다. 3) 실험 동물 각 군간에 약물 투여 시간 경과에 따른 음수량을 비교한 바, 약물투여 1주에서 각 군간에 유의한 차이는 없었다. 약물 토여 2주에서 fluoxetine 투여군, risperidone 0.1㎎ 투여군, 그리고 risperidone 0.5㎎투여군이 haloperidol 투여군과 비교하여 유의한 차이를 보였다. 약물투여 3주째에 fluoxetine투여군, risperidone 0.1㎎ 투여군, 그리고 risperidone 0.5㎎투여군이 haloperidol 투여군, vehicle과 비교하여 유의한 음수량의 저하를 보였다. 결 론 : 백서의 강박 행동은 fluoxetine, risperidone에 의해 효과적으로 억제되었으나 haloperidol에는 반응이 없었으므로, 임상에서 난치성 강박장애의 치료에 비정형 항정신병 약물 투여를 고려해 볼 수 있다고 제안한다. Objectives : This study was designed to evaluate the effects of risperidone on the schedule-induced polydipsia(SIP) which is one of animal model of obsessive-compulsive disorder in rats. We administered risperidone as a serotonin and dopamine blocking agent, fluoxetine as a selective serotonin reuptake inhibitor, and haloperidol as a dopamine antagonist to rats which showed schedule-induced polydipsic behaviour. Methods : Sprage-Dawley rats weighing 200∼250gm were individually housed and maintained and allowed free access to water. The rats were placed on a restricted diet. To induce polydipsia, rats were placed in the cage where a pellet dispenser automatically dispensed 90㎎ pellets on a fixed-time 60 seconds(FT 60s) feeding schedule over 150 minute test session per day. Water was available at all times in the cage. After 4 weeks of daily exposure to the FT 60s feeding schedule, experimental rats met a predetermined criterion for polydipsic behavior(greater than 3 times of water per session on average). 5 groups of rats were administered risperidone(0.1㎎/㎏, i.p), risperidone(0.5㎎/㎏, i.p), fluoxetine(5㎎/㎏, i.p), haloperidol(0.1㎎/㎏, i.p), and vehicle(1㏄/㎏, i.p) for 3 weeks. The rats were tested once a week to access schedule induced polydipsic behavior. Water bottles were weighed before and after the 150-minute test session. The chronic effects of administration of experimental drugs on schedule induced polydipsic behavior were analyzed with ANOVA and Scheffe test as a post-hoc comparison. In order to measure water consumption in non-polydipsic food-deprived rats, a separate group of rats(N=8) was individually housed and given a single bolus(14.5gm) of food per day which maintained them at their average body weight. Results : The results were as follows ; 1) After 4 weeks of scheduled feeding procedure, the experimental group showed significant differences than the bolus control in the amount of water consumption as compared with their average water intakes for 4 weeks. At the same periods, there were no differences between the experimental group and the bolus control in the body weight. 2) The fluoxetine group showed significant decrease in the amount of water intake at 1st, 2nd, and 3rd weeks of drug treatment as compared with their average amount of polydipsic water intakes. The risperidone 0.1㎎ group and the risperidone 0.5㎎ group showed significant decrease in the amount of water intake at the 3rd weeks of drug treatment as compared with their baseline of polydipsic water intakes. However, the haloperidol group and the vehicle control group showed no changes of amounts of water intake for 3 weeks of treatment as compared with their baseline of polydipsic water intakes. 3) The fluoxetine group(22.5±10.4ml) showed significantly lower amounts of water intake than haloperidol group(41.3±7.1ml) at 2nd weeks of drug treatment. And also the fluoxetine group(18.8±3.5ml) showed significantly lower amounts of water intake than the haloperidol group(35.0±11.7ml) and the vehicle control(34.4±6.8ml) at 3rd weeks of drug treatment. The risperidone 0.1㎎ group and the risperidone 0.5㎎ group showed significantly lower amounts of water intake than the haloperidol group(35±11.7ml) at 2nd weeks and the vehicle control(37.5±12.5, 34.4±6.8ml) at 2nd and 3rd weeks of drug treatment. Conclusions : Above findings suggest that the fixed time feeding procedure for schedule induced polydipsia could be applied as an effective animal model of obsessive compulsive disorder for the evaluation of pharmacological challenge study. We confirmed that chronic treatment with risperidone revealed antipolydipsic effect as effective as fluoxetine on the schedule-induced polydipsic behaviour but the onset of effect was later than fluoxetine.

세로토닌성 항우울제가 백서의 Schedule-Induced Polydipsia에 미치는 영향

이기철,이정호,박중섭,최영민,전성일,정홍경,하준명,정재현 대한생물치료정신의학회 1999 생물치료정신의학 Vol.5 No.2

Object : Schedule-induced polydipsia is considered as an animal model of obsessive-compulsive disorder inrats. The authors evaluated the chronic effects of fluoxetine and clomipramine as serotonergic antidepressants and haloperidol as dopaminergic antagonist on the schedule-induced polydipsia in rat.Methods : Spraque-Dawley rats weighing 200-250gm were individually housed, maintained and allowed free access to water for 1 week. And then the rats were placed on a restricted diet. To induce polydipsia, rats were placed in automatic cage where a pellet dispenser automatically dispensed 90mg pellets on a fixed-time 60 seconds(FT 60s) feeding schedule over 150-minute test session for a day. Water was available at all times during the feeding schedule in automatic cage. After 4 weeks of daily exposure to the FT 60s feeding schedule, experimental rats met a predetermined criterion for polydipsic behavior(greater than 3 times of water per session on average). 4 groups of rats were administered fluoxetine(5mg/kg/i.p.), clomipramine(5mg/kg/i.p.), haloperidol(0.1mg/kg/i.p.), vehicle(1cc/kg/i.p.) for 3 weeks. Rats were tested once a week to access schedule induced polydipsic behavior. The chronic effects of experimental drugs on schedule induced polydipsic behavior were analyzed with repeated analysis of variance and Scheffe test as a post-hoc comparison.In order to measure water consumption in non-polydipsic food-deprived rats, a separate group of rats(N=8) were individually housed and given a single bolus(14.5 gm) of food per day which maintained them at their average body weight.Results and Conclusion : The results were as follows ;1) After 4 weeks of daily feeding procedure with fixed time schedule for 60 seconds per day, the experimental group showed significant differences than the control in the amount of water consumption as compared with their baseline water intakes. At the same periods, there were no differences between the experimental group and the control in body weight. 2) The clomipramine treated group and the fluoxetine treated group showed significant decrease in the amount of water intake as compared with their baseline of polydipsic water intakes for 3 weeks of treatment. However, the haloperidol treated group and the vehicle control group showed no changes of amounts of water intake for 3 weeks of treatment as compared with their baseline of polydipsic water intakes. 3) At 2 weeks of drug treatment, clmipramine treated group(16.88±6.51ml) and the fluoxetine treated group(22.50±10.35ml) showed significantly lower amounts of water intake than the haloperidol treated group (41.25±7.06ml) or vehicle control group(37.50±12.54ml). And also the clomipramine treated group(13.75±5.18ml) and the fluoxetine treated group(18.75±3.54ml) showed significantly lower amounts of water intake than the haloperidol group(35.00±11.65ml) and the vehicle control(34.38±6.78ml) at 3 weeks of drug treatment. Above findings suggest that the fixed time feeding procedure for schedule-induced polydipsia as an animal model of obsessive compulsive disorder was effective to the evaluation of pharmacological challenge study. The author confirmed that schedule-induced polydipsia was successfully decreased for 3 weeks of administration of clomipramine and fluoxetine but there was no response to haloperidol.

Clozapine이 백서의 Schedule-Induced Polydipsia에 미치는 영향

이기철,정홍경,이정호,홍승범,최영민,전성일,정재현,하준명 대한생물치료정신의학회 2000 생물치료정신의학 Vol.6 No.2

Object : This study was designed to evaluate the effects of clozapine which is one of most useful atypical antipsychotics in the schedule-induced polydipsic rat which is an animal model of obsessive-compulsive disorder. Methods : Spraque-Dawley rats were placed in automatic cage where a pellet dispenser automatically dispensed 90mg pellets on a fixed-time 60 seconds(FT- 60s) feeding schedule over 150-minute test session for 4 weeks. After 4 weeks of daily exposure to the FT-60s feeding schedule, experimental rats met a predetermined criterion for polydipsic behavior(greater than 3 times of water per session on average). Rats were stratified into clozapine(0.34mg/kg,i.p.), clozapine(14.63mg/kg,i.p.), clomlpramine(5mg/kg,i .p.), and vehicle (1cc/kg,i.p.) group and treated with each drugs for 3 weeks. To identify the non-polydipsic food-deprived rats, a separate group of rats(N=8) were individually housed and given a single bolus(14.5gm) of food per day which maintained them at their average body weight. Results : The results were as follows ; 1)After 4 weeks of scheduled feeding procedure, the experimental group showed significant differences than bolus control in the amount of water consumption as compared with their baseline of water intakes for 4 weeks. At the same periods, there were no differences between the experimental group and bolus control in the borty weight. 2)The clomipramine group, the clozapine 0.34mg group and the clozapine 14.63mg group showed significant decrease in the amount of water intake for at 2nd & 3rd week of drug treatment as compared with their baseline of polydipsic water intakes. But, the vehicle control group showed no changes of amounts of water intake for 3 weeks of treatment as compared with their baseline of polydipsic water intakes. Conclusion : Above findings suggest that the fixed time feeding Procedure for Schedule induced polydipsia as an animal model of obsessive compulsive disorder was effective to the evaluation of pharmacological challenge study. In clinical situation, the authors suggest that atypical antipsychotic drugs which act as serotonin and dopamine receptor antagonist may be helpful to improve the symptoms of the patients with treatment refractory obsessive-compulsive disorder.