Antidepressant-like effect of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice forced swim test

被引:196
作者
Khisti, RT [1 ]
Chopde, CT [1 ]
Jain, SP [1 ]
机构
[1] Dept Pharmaceut Sci, Nagpur 440010, Maharashtra, India
关键词
neurosteroid; 3; alpha; 5 alpha THP; allopregnanolone; metyrapone; 4 '-chlorodiazepam; FGIN; 1-27; fluoxetine; GABA(A)-receptor; antidepressant;
D O I
10.1016/S0091-3057(00)00300-2
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
The present study aimed to examine the antidepressant-like effect of the neurosteroid 3 alpha -hydroxy-5 alpha -pregnan-20-one (3 alpha, 5 alpha THP) using the forced swim test in mice. Intracerebroventricular (ICV, 1 or 2 mug/mouse) or intraperitoneal (IP, 0.5, 1, or 2 mg/kg) administration of 3 alpha, 5 alpha THP dose-dependently reduced the duration of immobility in forced swim test without accompanying changes in ambulatory or rearing behaviors in the open-field test. The antidepressant-like effect of 3 alpha, 5 alpha THP (1 mug/mouse, ICV) was potentiated by prior administration of the GABAA receptor agonist, muscimol (0.5 mg/kg, IF) and blocked by prior administration of GABAA receptor antagonist, bicuculline (1 mg/kg, IF). Administration of the agonist at diazepam binding inhibitor receptors, 4'-chlorodiazepam (4'CD, 15 mg/kg, IF) or N,N-di-n-hexyl-2-(4-fluorophenyl)-indol-3-acetamide (FGIN 1-27, 1 or 2 mug/mouse, ICV), the 11 beta -hydroxylase inhibitor, metyrapone (150 mg/kg, IP and 1 or 2 mug/mouse, ICV) and the selective serotonin reuptake inhibitor (SSRI), fluoxetine (20 mg/ kg, IF), which are known to increase the endogenous level of neurosteroids, also reduced the duration of immobility in forced swim test. The tricyclic antidepressant, imipramine (20 mg/kg, TP), which does not increase the 3 alpha, 5 alpha THP in the brain, also reduced the immobility time. While the antidepressant- like effect of fluoxetine, which is known to selectively increase the brain content of 3 alpha, 5 alpha THP, was either blocked partially by bicuculline (1 mg/kg, IF) or potentiated by muscimol (0.5 mg/kg, IF), the antidepressant-like effect of imipramine was not modified by bicuculline. These results demonstrate the antidepressant-like effect of the neurosteroid 3 alpha, 5 alpha THP, and suggest further evaluation for its development as a new class of antidepressant drug. (C) 2000 Elsevier Science Inc. All rights reserved.
引用
收藏
页码:137 / 143
页数:7
相关论文
共 53 条
[1]  
Backstrom T, 1985, Acta Obstet Gynecol Scand Suppl, V130, P19
[2]  
Backstrom T, 1995, CIBA F SYMP, V191, P171
[3]  
Bicikova, 1998, Endocr Regul, V32, P87
[4]   Allopregnanolone in women with premenstrual syndrome [J].
Bicíková, M ;
Dibbelt, L ;
Hill, M ;
Hampl, R ;
Stárka, L .
HORMONE AND METABOLIC RESEARCH, 1998, 30 (04) :227-229
[5]  
Bullock AE, 1997, J NEUROCHEM, V68, P2412
[6]   The hyperphagic effect of 3 alpha-hydroxylated pregnane steroids in male rats [J].
Chen, SW ;
Rodriguez, L ;
Davies, MF ;
Loew, GH .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1996, 53 (04) :777-782
[7]  
French-Mullen JM, 1994, J NEUROSCI, V14, P1963
[8]   THE NEUROSTEROID 3-ALPHA,5-ALPHA-THP HAS ANTISEIZURE AND POSSIBLE NEUROPROTECTIVE EFFECTS IN AN ANIMAL-MODEL OF EPILEPSY [J].
FRYE, CA .
BRAIN RESEARCH, 1995, 696 (1-2) :113-120
[9]  
GERNER RH, 1981, AM J PSYCHIAT, V138, P1098
[10]  
GOLD BI, 1980, AM J PSYCHIAT, V137, P362