Alterations of norepinephrine metabolism in rat locus coeruleus neurons in response to axonal injury.

Adult male Sprague-Dawley rats were injected in the right cerebral hemisphere with the neurotoxin 6-hydroxydopamine (6-OHDA) at a site which interrupted the noradrenergic axons ascending from the locus coeruleus (LC). Distal to the injection site ('posterior cortex'), levels of norepinephrine (NE), dopamine-beta-hydroxylase (D beta H) and tyrosine hydroxylase (TH) fell to 39-42% of control levels ipsilateral to the lesion over the first 25 days, while contralateral levels fell to 32-73% of control during this time. These changes were paralleled by a 63% decrease in the high affinity uptake of [3H]NE in the ipsilateral posterior cortex at 12 days after the lesion. Both ipsilateral and contralateral levels of NE and D beta H fell in the LC during this time, while LC TH showed variable increases and decreases in activity. At 3 months after right cortical 6-OHDA injections, posterior cortical levels of NE, D beta H and TH, as well as the high affinity uptake of [3H]NE, had returned to control levels suggesting that some type of regeneration or axonal sprouting had occurred. Axonal transport of D beta H and TH was assessed by measuring the accumulation of enzyme activity proximal to a 6-OHDA lesion made in the more caudal portion of these same LC axons. Transport of D beta H fell to 7-40% of control from 2 to 24 days and rose to 160% of control by 3 months after the lesion. TH transport was decreased to only 61% of control only at 24 days and returned to control levels by 3 months. These studies document that there is independent regulation of the metabolism of the NE synthetic enzymes, D beta H and TH, during the degeneration and subsequent regeneration or collateral sprouting of injured distal axons of LC noradrenergic neurons.