CHRONIC INFUSION OF NERVE GROWTH-FACTOR INTO RAT STRIATUM INCREASES CHOLINERGIC MARKERS AND INHIBITS STRIATAL NEURONAL DISCHARGE RATE

New strategies have recently been developed where infusion of neurotro phic factors into the brain can rescue different populations of neuron s. Infusion of nerve growth factor (NGF) has been used in combination with transplants of chromaffin tissue to the striatum in the rat model of Parkinson's disease as well as to patients suffering from Alzheime r's disease. In this study we have evaluated the distribution of recom binant human NGF (rhNGF) in different brain areas and evaluated morpho logical and electrophysiological effects after continuous infusion for 2 weeks of rhNGF (500 mu g/ml) into the striatum of normal rats. One week after termination of rhNGF infusion, NGF levels in the infused st riata were IO-fold increased while in contralateral striata normal lev els were found. Extracellular recordings from striatal neurons reveale d a significantly decreased spontaneous firing rate (0.76 +/- 0.07 Hz) in rats infused with rhNGF compared to vehicle-infused control animal s (1.36 +/- 0.16 Hz). Local application of rhNGF during recordings sho wed no direct inhibitory effect of NGF on neuronal discharge rate. Imm unohistochemistry, using antibodies against acetyl cholinesterase (ACh E) and glial fibrillary acidic protein (GFAP), revealed a 38.7 +/- 7.0 % increase in optical density of AChE immunoreactivity close to the NG F source and an increase in GFAP-positive profiles that was restricted close to the implanted dialysis fibre. In situ hybridization showed a n increase in mRNAs for choline acetyltransferase, trkA, p75 and musca rinic m2 receptor in the large neurons of rhNGF-infused striatum. Mess enger RNAs for m1 and m4 receptors in striatal neurons were not change d. Thus, chronic infusion of rhNGF into the striatum caused a choliner gic hyperinnervation and reduced spontaneous activity of striatal neur ons.