Cell responsiveness to neurotransmitter or hormones is modulated up or down as a function of normal increases or decreases in synaptic traffic, contributing to long term changes in function and the plasticity of neuronal networks. It is likely to mediate responses to surgical, pharmacological or accidental disruption of neuronal activity: for example, spinal cord injury can lead to bladder and kidney supersensitivity and drug treatments can lead to tardive dyskinesia or psychosis. These changes also may partially explain why protracted drug administration is needed for treatment of affective disorders. However, little attention has been directed toward examination of the mechanisms underlying such phenomena except in the case of adrenergic denervation of smooth muscle and in the special, atypical case of denervated skeletal muscle. A much better model of what happens in the CNS when one input is altered would be provided by studies of a tissue with multiple innervation. The studies proposed here will investigate the consequences of removing a single input from dually innervated tissue, using the rat parotid gland as a model system. Parasympathetic denervation supersensitivity has been documented in vivo for the rat parotid gland, and dissociated acinar cells have been used advantageously as an in vitro system for elucidating the mechanism of phosphatidyl inositide turnover and fluid and electrolyte secretion. We have shown that supersensitivity can be studied in vitro in this model; parasympathetic denervation supersensitivity, a non-specific phenomenon affecting muscarinic, alpha-adrenergic and substance P responses, involves post-receptor mechanisms that lie distal to phospholipase C activation and modulate free cytoplasmic calcium (Cai) responses. The properties of receptor-activated Cai; elevation in individual acinar cells frofn control and denervated glands will be studied, using Ca-sensitive fluorescent dyes and image analysis techniques to evaluate the role of cellular heterogeneity and cell volume in establishing cellular sensitivity. The involvement of intracellular calcium release in the supersensitive response will be examined in intact cells, and the sensitivity of intracellular calcium stores to release by IP3 will also be directly evaluated in permeabilized cells. These studies should provide insight into mechanisms of target cell plasticity which are mediated by changes in neuronal input or activity.
