Dopamine neurons project to dorsal striatum from substantia nigra (SN), and project to olfactory tubercle, nucleus accumbens, ventral striatum, prefrontal cortex and other portions of the cortex and limbic system from the ventral tegmental area (VTA). The SN system is involved in locomotion, and the VTA systems apparently affect motivation, perception and mood. Dopamine neuronal firing and synthesis in SN neurons and some VTA neurons appear to be regulated by autoreceptors, presumably D2 type, whereas VTA neurons to prefrontal cortex may lack such autoreceptors. Autoreceptors are believed to be important in actions and side effects of dopamine agonists and antagonists used in the treatment of Parkinson's disease and schizophrenia. In this program project grant, we will attempt to determine factors which regulate dopamine cell firing, dopamine synthesis and release, and dopamine receptor-mediated responses in the several regions of brain where SN and VTA dopamine neurons project, and we will assess in each region the presynaptic and postsynaptic consequences of administration of dopamine agonists and antagonists. Studies will include regulation of tyrosine hydroxylase activity and phosphorylation, characterization of dopamine receptor subtypes and the effects on the adenylate cyclase system of activation of these receptors, regulation of dopamine release, relation between locomotor activity and other behaviors and in vivo dopamine release from different brain regions, the role of autoreceptors in dopamine neuron cell firing and dopamine release, and the molecular basis of the trans-synaptic induction of tyrosine hydroxylase. Various fetal brain structures containing catecholamine cell bodies, or adrenal medulla tissue, will be transplanted either in oculo or into brain regions in situ to which dopamine neurons normally project. The in oculo tissues will be permitted to develop and innervate the iris, or they will be placed adjacent to a transplant of a fetal brain region which normally receives dopamine projections. When fully developed, the properties of these in oculo and in situ transplants with respect to morphological development and synapse formation, neural firing, dopamine synthesis and release, dopamine receptors and dopamine-sensitive adenylate cyclase will be determined. Modulation of the various functions and behaviors of the transplants by dopamine agonists and antagonists and other substances will be ascertained to determine whether the pharmacologic responses of these neurons are intrinsic properties or whether they are determined by the nature of the target tissue to which the neurons project.
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