Evidence from clinical observations as well as from experimental investigations indicates that subtotal damage to monoaminergic neurons produces few enduring functional impairments despite considerable evidence for their involvement in a wide variety of physiological and behavioral processes. We have proposed that this apparent paradox results from the capacity for """"""""synaptic homeostasis"""""""" which exists in these systems and which leads to compensatory events occurring after partial injury. Our research will focus on describing at the cellular level the initial deficits, recovery of function and residual deficits produced by subtotal destruction of the dopaminergic component of the nigrostriatal bundle and to explore the neurochemical bases of those phenomena. This work will utilize an in vitro model to address four issues. (1) The impact of the injury on dopaminergic function: Striatal slices exposed to field stimulation will be used to examine the influence of dopamine (DA) and of partial injury produced by 6-hydroxydopamine on acetylcholine (ACh), GABA, and cAMP efflux. Studies will be carried out as a function of post-operative time and lesion size. (2) Lesion-induced changes in the synthesis, release, and reuptake of DA: We will measure DA efflux from stimulated slices and determine the relative contribution of altered release and reuptake. We also will begin to examine the genetic regulation of tyrosine hydroxylase synthesis. (3) Lesion-induced changes in responsiveness of striatal targets to DA: We will focus on D-2 receptor mediated events, examining changes in agonist-induced ACh efflux and in D-2 binding sites. We also hope to begin an analysis of the importance of changes in signal transduction distal to the binding site itself. (4) The ability of treatments to extend recovery of striatal function: Possible modes of """"""""therapy"""""""" to be examined include DOPA, tyrosine, pterine cofactor supplementation as well as in vivo exposure to stressors such as insulin-induced glucoprivation. These results should provide insights into the neurobiology of moneaminergic systems under normal conditions and after damage, as well as information of relevance to the detection and treatment of subclinical brain damage in those psychiatric and neurological disorders involving abnormalities of monoamine-containing systems.
