טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentDanovich Ilana
SubjectThe Influence of Chronic Treatment with Clozapine and other
Antipsychotic Drugs on Peripheral-Type
Benzodiazepine Receptor Expression
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moshe Gavish


Abstract

The peripheral benzodiazepine receptor (PBR) was demonstrated to be involved in the process of steroid biosynthesis, in both peripheral steroidogenic tissues and in glia cells in the brain. It was shown that the atypical antipsychotic drug clozapine increases the brain levels of the neurosteroid allopregnanolone in the rat brain. In the current study, we investigated the influence of chronic treatment with clozapine and other antipsychotic drugs on PBR binding characteristics and protein expression in rats and in cell cultures. Male Sprague-Dawley rats were treated with clozapine (20 mg/kg), risperidone (0.5 mg/kg), thioridazine (20 mg/kg), or sulpiride (20 mg/kg) for 21 days, followed by 7 days drug-free regime. Clozapine induced significant increases in PBR binding capacity in both central tissues (hippocampus and hypothalamus) and peripheral steroidogenic tissues (adrenal and testis), whereas other antipsychotic treatments did not show such pronounced effects on PBR binding. Protein levels of PBR components, isoquinoline binding protein (IBP) and voltage dependant anion channel (VDAC), were not altered by the antipsychotic compounds. Our in vitro results supported our in vivo findings. Clozapine significantly increased PBR binding density in C-6 rat glioma cells and in MA-10 mouse Leydig tumor cells, while the typical antipsychotic sulpiride had no effect on PBR binding density in both cell lines. In addition, we examined whether the drug induced changes in PBR binding are accompanied by parallel alterations in steroidogenesis. Clozapine, thioridazine, risperidone, and PBR specific ligand PK11195 significantly increased progesterone synthesis in MA-10 Leydig cells. Our findings suggest that the regulatory effect of clozapine on PBR expression might be involved in one of the molecular pathways responsible for the unique clinical profile of this antipsychotic agent.