Reversible reduction of tyrosine hydroxylase enzyme protein during the retrograde reaction in mesolimbic dopaminergic neurons

Abstract

Changes in the activity and amount of the neurotransmitter synthesizing enzyme tyrosine hydroxylase (TH) were measured in dopaminergic (DA) neurons of the A10-mesolimbic system of the rat following electrolytic lesions of their axons. Unilateral hypothalamic lesions in close proximity to the cell bodies resulted, within 24–48 h, in a permanent anterograde reduction of TH to 10–20% of control in the ipsilateral olfactory tubercle and nucleus accumbens. The retrograde reaction in the A10-DA nerve cell bodies was characterized by an initial increase in TH activity to 133% by 24–48 h followed by a gradual and permanent fall to 50% of control by day 14 due to retrograde cell death of DA neurons. In contrast, lesions of DA axon terminals in the olfactory tubercle resulted in a reversible retrograde reduction of TH activity in the A10. The enzyme activity declined during the first 7 days to 70% of control and then gradually recovered, reaching control levels by 28 days after the operation. The reduction in TH activity in the A10 was demonstrated by immunochemical titration with a specific antibody to TH to be entirely due to reduced amounts of enzyme protein. We conclude that in mesolimbic DA neurons: (a) the anterograde reaction is chaacterized by a rapid and permanent decline of TH in degenerating terminals; (b) the retrograde reaction is dependent upon the proximity of the lesion to the nerve cell body, and (c) a reversible reduced accumulation of TH characterizes the retrograde reaction in response to lesions of distal axons. The reaction of DA neurons of the mesolimbic system to axonal injury is comparable to that of the nigrostriatal system.