These proposed experiments are designed to investigate postnatal changes in the neurophysiology, neuroanatomy and neuropharmacology of neostriatal and substantia nigra dopaminergic neurons in the developing rat. There are many reasons for needing to understand the postnatal ontogeny of neuronal function in the basal ganglia. One is the recent finding that surviving neurons in grafts of fetal neurons to adult hosts, currently used as both an experimental tool as well as a novel clinical approach to treatment of neurodegenerative disorders such as Parkinson's, Alzheimer's and Huntington's disease, exhibit characteristics much more similar to early neonatal neurons in situ than their corresponding adult counterparts. In order to understand the scope and limitations of neuronal grafting as a clinical tool, it is necessary to first understand the neurophysiological properties of immature basal ganglia neurons that occur during the postnatal period. A second important implication of this work is in trying to understand the physiological bases for certain developmental disorders of learning and behavior, for example, attention deficit disorder with hyperactivity (ADDH), and their pharmacological management with stimulants. The experiments utilize extracellular and intracellular single unit recording in vivo to chart the postnatal development of spontaneous and evoked activity of neostriatal and substantia nigra dopamine neurons. Intracellular recordings will be performed with microelectrodes containing biocytin which will be injected into each neuron at the end of the physiological experiments to reveal the entire structure of the neuron, thus allowing a correlation of the postnatal development of neuronal physiology with morphology. Other experiments will use PHA-L to label afferents to substantia nigra and neostriatal neurons, some of which will be subsequently intracellularly labeled with biocytin. Inspection of the tissue at the light and electron microscopic levels will allow us to determine how the pattern of innervation of these important afferents develops in normal postnatal brain, as well as to determine the effect of the nigrostriatal dopamine input on the development of cortical and thalamic synaptic inputs to neostriatum by using 6-OHDA to destroy the dopaminergic inputs. The last major focus of these studies is to use in vitro intracellular recordings to determine the sites and mechanisms of action whereby amphetamine and related stimulants produce a paradoxical excitatory effect on the firing of nigral dopaminergic neurons in early postnatal rats instead of the inhibition that is seen in adults. This phenomenon may have special significance to the mechanism of the paradoxical behavioral effects of amphetamine-like compounds in the treatment of ADDH, as well as to the phenomenon of marked differences in the effects of stimulant drugs on mature versus immature nervous systems.
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