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The overall goals of this research project is to study the role of the adult neurogenesis in the pathophysiology of the epilepsy and drug addiction and possibilities of its pharmacological regulation. Pharmacological control of the adult brain neurogenesis represents a novel approach referred to as restorative pharmacology and might have a potential to revolutionize the treatment of the neurodegenerative diseases epilepsy, drug addiction. Adult neurogenesis has been demonstrated in in the dentate gyrus of hippocampus and subventricular zone in several mammals including humans (P.S. Eriksson et al., Nature Med., 1998, vol. 4, p.1313-1317). Recent experiments on the laboratory animals showed that environmental stimuli and several neuroactive compounds can induce changes in the neureogensis. It was also demonstrated that epilepsy and repeated treatmet with narcotic drugs can induce changes in the neurogenesis. The role of hippocampal neurogenesis in epilepsy and drug addiction state is not clear. We hypothesize that increase in neurogenesis in some pathological conditions might led to the remodeling of the dentate gyrus is involved in the further developmet of disease or the srtate of addiction. Accordingly, we propose the pharmacological regulation of neurogenesis directed toward facilitation of maturation of the newborn cells and establishment of normal synaptic connections could be beneficial in conditions related to the neurodegeneration, epilepsy and drug dependence. In our experiments, the process of neurogensis will be studied in details on two models: 1) experimental model of progressive myoclonic epilepsy, which is based on the genetic defect in cystatin B gene. Trangenic mice lacking cystatin B will be used; 2) animal models of addiction induced by ethanol and cocaine. The regulatory role of growth factors and neurotransmitters: serotonin, GABA and glutamate on the process of neurogenesis will be studied. The effects of several drugs including neurosteroids on the neurogenesis will be studied. The project will have real practical outcome resulting in the development of new effective drugs, which could be used in the treatment of pathologies (epilepsy, drug addiction) associated with abnormal neurogenesis. |