This project involves studies of plasticity and functional consequences of changes in the striatal afferent systems, especially the dopaminergic afferents derived from the substantia nigra and the glutamatergic afferents derived from the cerebral cortex. Techniques employed involve: (i) transplanting tissues containing catecholamines or L-DOPA (i.e., adrenal medulla, tumor cells, genetically altered cells, and embryonic brain tissue) into the brain, (ii) biochemical and pharmacological studies, and (iii) studies using tissue culture models. The purpose of these experiments is in part to: (A) elucidate the properties of these tissues after transplantation and the response of the host brain to the transplanted tissues, and (B) to investigate mechanisms of neuronal adaptation and plasticity in response to injury and chronic pharmacological treatments. Specifically, (A) these experiments employ animal models to: (1) develop the techniques of brain tissue transplantation for clinical use in Parkinson's disease; (2) develop brain tissue transplantation techniques which eventually may be applicable to other disorders such as schizophrenia and epilepsy, if and when these disorders become sufficiently understood to permit such applications; (3) develop alternate cell types, such as immortalized neurons, for transplantation into the brain and corresponding in vitro model studies of cellular differentiation and cell-cell interactions; and (4) elucidate the factors controlling brain development and brain response to injury or impairment, with particular emphasis on the nigrostriatal dopamine system. (B) The second purpose of these experiments is primarily aimed at elucidating the interactions between functions of: (a) the glutamate-mediated corticostriatal system and related anatomical systems, and (b) dopaminergic systems, including the nigrostriatal system; and the functional effects of stimulant and neuroleptic drugs. The ultimate purpose of these studies is to enhance our understanding of the mode of action of neuroleptics and possibly brain dysfunction in schizophrenia. Secondary purposes are to enhance our understanding of the mechanisms of stimulant drug effects and alcohol addiction; to develop compounds with potential utility for the acute treatment of stimulant overdose, schizophrenia, and seizure disorders; and to understand the possible forms of plasticity in the corticostriatal system. During the past reporting year, significant progress has been made in these areas.
