서론 50 Korean J Psychopharmacol 1998;91:49-57

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1 KISEP Original Articles Haloperidol, Clozapine 및 Haloperidol과 Serotonin 성제제병합약에의한흰쥐뇌 FOS 면역반응성 ABSTRACT 김광수 박원명 서상원 FOS-like Immunoreactivity in Rat Brain Induced by Haloperidol, Clozapine, and Haloperidol Combined with Serotonergic Agents Kwang-Soo Kim, MD, Won-Myong Bahk, MD and Sang-Won Seo, MD Neuroscience Center, Catholic Medical Center, Department of Neuropsychiatry, St. Marys Hospital, Catholic University Medical College, Seoul, Korea ObjectivesThe purpose of this study was to investigate the differences between potential neuroanatomical sites of action of 1 a typical antipsychotic drug haloperidol, 2 an atypical antipsychotic drug clozapine, and 3 threecombinations of both haloperidol and serotonergic agents haloperidolbuspirone, haloperidol cyproheptadine, haloperidolfluoxetine by comparing their effects on c-fos expression in the rat brain. MethodsTwenty-four Wistar rats of male sex, weighing g, were divided into 6 groups according to the type of the agents tested [vehicle 0.14 M acetic acid 1 ml/kg, haloperidol 1.0 mg/kg, clozapine 20 mg/kg, haloperidolbuspirone 1.0 mg/kg1.0 mg/kg, haloperidolcyproheptadine 1.0 mg/kg1.0 mg/kg, haloperidolfluoxetine 1.0 mg/kg0.25 mg/kg]. The brain of variously treated rat was examined 2 hours after subcutaneousely injection in the neck. The brain was removed immediately after perfusion with 4% paraformaldehyde and placed in a fresh fixative of the same solution. After 12-hr fixation, brain sections 30 m of the areas including the medial prefrontal cortex, nucleus accumbens, and lateral striatum were stained by Fos immunohistochemistry, and subjected to light microscopic analytical observations. Results1 The number of Fos-positive neurons in the medial prefrontal cortex was significantly increased in the clozapine, haloperidolbuspirone, haloperidolcyproheptadine, and haloperidolfluoxetine treated groups than in the control group p0.05. But, the haloperidol treated group shows no significant difference. 2 The number of Fos-positive neurons in the nucleus accumbens was significantly increased in the haloperidol, clozapine, haloperidolbuspirone, haloperidolcyproheptadine, haloperidolfluoxetine treated groups than in the control group p The number of Fos-positive neurons in the lateral striatum was significantly increased in the haloperidol, haloperidolbuspirone, haloperidolcyproheptadine, haloperidolfluoxetine treated groups than in the control group p0.05. But, the clozapine treated group shows no significant difference. Conclusion These results suggest that differential expression of c-fos in rat brain induced by haloperidol, clozapine, and haloperidol combined serotonergic agents is associated with their clinical and pharmacological differences. Korean J Psychopharmacol 1998;91:49-57 KEY WORDSc-fos Haloperidol Clozapine Haloperidol combined serotonergic agents. 49

2 서론 50 Korean J Psychopharmacol 1998;91:49-57

3 1. 연구대상 연구대상및방법 2. 연구방법 51

Haloperidol, Clozapine 및 Haloperidol과 Serotonin성 제제의 뇌 FOS 면역반응성

Photomicrographs of Fos immunoreactivity in the medial prefrontal

Photomicrographs of Fos immunoreactivity in the nucleus accumbens

2 hours after injection of (3A) vehicle (1.

0 mg/kg), (3C) clozapine (2and (3D) haloperidol (1.fluoxetine (0.

haloperidol과 fluoxetine 병 4) 통계처리 뇌 부위별로 각 약물을 주사후 Fos( ) 신경원 수의 차

미만으로 하였다. 결 과 합약을 투여한 군에서 대조군보다 유의하게 증가하였다 (p<0.05)(table 1).

4 Haloperidol, Clozapine 및 Haloperidol과 Serotonin성 제제의 뇌 FOS 면역반응성 Fig. 1. Photomicrographs of Fos immunoreactivity in the medial prefrontal cortex 2 hours after injection of (1A) vehicle (1.0 ml/kg), (1B) haloperidol (1.0 mg/kg), (1C) clozapine (20 mg/kg) and (1D) haloperidol (1.0 mg/kg) cyproheptadine (1.0 mg/kg). Photomicrographs of Fos immunoreactivity in the nucleus accumbens 2 hours after injection of (2A) vehicle (1.0 ml/kg), (2B) haloperidol (1.0 mg/kg), (2C) clozapine (20 mg/kg) and (2D) haloperidol (1.0 mg/kg) buspirone (1.0 mg/kg). Photom-icrographs of Fos immunoreactivity in the lateral striatum 2 hours after injection of (3A) vehicle (1.0 ml/kg), (3B) haloperidol (1.0 mg/kg), (3C) clozapine (20 mg/kg) and (3D) haloperidol (1.0 mg/kg) fluoxetine (0.25 mg/kg). The arrow indicated Fos-positive neurons. Scale bar 100 μm. 로 확대하여 세었다.26) haloperidol과 buspirone 병합약, haloperidol과 cyproheptadine 병합약 및 haloperidol과 fluoxetine 병 4) 통계처리 뇌 부위별로 각 약물을 주사후 Fos( ) 신경원 수의 차 이를 one-way ANOVA와 posthoc Tukey s test로 유 의성 검증을 하였으며, 유의수준은 5% 미만으로 하였다. 결 과 합약을 투여한 군에서 대조군보다 유의하게 증가하였다 (p<0.05)(table 1). 그러나 haloperidol을 투여한 군은 대조군과 비교하여 유의한 차이가 없었다(Table 1). 2. Haloperidol, clozapine 및 haloperidol과 serotonin성 제제 병합약에 의한 측좌핵 c- fos 발현 측좌핵의 Fos( ) 신경원 수는 haloperidol, clozapine, 1. Haloperidol, clozapine 및 haloperidol과 seroto- haloperidol과 buspirone 병합약, haloperidol과 cypr- nin성 제제 병합약에 의한 내측 전전두피질 c-fos oheptadine 병합약 및 haloperidol과 fluoxetine 병합 발현 약을 투여한 군 등 5개 실험군 모두에서 대조군보다 내측 전전두피질의 Fos( ) 신경원 수는 clozapine, 52 유의하게 증가하였다(p<0.05)(Table 1). Korean J Psychopharmacol 1998;9(1):49-57

5 Table 1. Effects of haloperidol, clozapine, and haloperidol combined with serotonergic agents on the number meansdof Fos-positive neurons within a 500 m500 m area of the medial prefrontal cortex MP, nucleus accumbens NA, and lateral striatum LS Drugs MP NA LS Control 0.14 M acetic acid 1.0 ml/kg Typical antipsychotics Haloperidol 1.0 mg/kg * * Atypical antipyschotics Clozapine 20 mg/kg * * Haloperidol combined with serotonergic agents Haloperidol1.0 mg/kgbuspirone1.0 mg/kg * * * Haloperidol1.0 mg/kgcyproheptadine1.0 mg/kg * * * Haloperidol1.0 mg/kgfluoxetine0.25 mg/kg * * * Asterisks * indicate statistically significant differences from the vehicle control p Haloperidol, clozapine 및 haloperidol과 serotonin성제제병합약에의한외측선조체 c- fos 발현 고찰 53

6 54 Korean J Psychopharmacol 1998;91:49-57

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1. 연구대상 대상및방법 2. 연구방법 1) Fluoxetine 의병합투여 2) 임상반응평가 3) 통계분석 1. 인구학적특성 결 2. 정신병리의변화 3. 추체외로부작용의변화 과

1. 연구대상 대상및방법 2. 연구방법 1) Fluoxetine 의병합투여 2) 임상반응평가 3) 통계분석 1. 인구학적특성 결 2. 정신병리의변화 3. 추체외로부작용의변화 과 KISEP Original Articles 생물정신의학 Vol. 4, No. 1, June 1997 Fluoxetine과 Haloperidol의병합투여시정신병리및추체외로증상의변화 이민수 * 한창수 * 김제원 ** 원경식 ** 곽동일 ** Changes of Psychopathology and Extrapyramidal Symptoms When Co-administering