6-Hydroxydopa: A Precursor-Neurotoxin with Relative Selectivity for Noradrenergic Neurons

Abstract

The selective neurotoxin 6-hydroxydopa (6-OHDOPA) was developed because of the correct assumption that it could, with some advantage, replicate actions of the newly discovered selective neurotoxin 6-hydroxydopamine (6-OHDA). 6-OHDOPA is a highly selective neurotoxin, targeting primarily noradrenergic nerves. By this, 6-OHDOPA is able to produce a chemical sympathectomy by destroying axonal tracts from sympathetic paraganglia as well as noradrenergic nerve terminals in peripheral organs and tissues. The sympathectomy can be produced when 6-OHDOPA is administered to either perinatal or adult animals. The effect, however, is not permanent, as the sympathetic nervous system fully regenerate to reinnervate the periphery in approximately 6 weeks. In the central nervous system (CNS), peripherally administered 6-OHDOPA has relative selectivity for noradrenergic neurons, predominately producing destructive effects on the locus coeruleus, the largest noradrenergic nucleus in the brain, having long axonal projections to forebrain, hippocampus, and cerebellum. Administered in high dose to adult mice or rats, 6-OHDA produces near total noradrenergic denervation of hippocampus, approximately 90% noradrenergic denervation of neocortex and cerebellum. When administered in high dose to perinatal rodents, a similar noradrenergic denervation spectrum is seen for hippocampus, neocortex, and cerebellum, and overtly damages neuronal perikaryal in the distal locus coeruleus. However, in time regenerated axons from locus coeruleus regrow short axons to produce neoinnervation and ultimate hyperinnervation of hindbrain regions, pons and medulla, and two-fold hyperinnervation of cerebellum. Effects of 6-OHDOPA on other noradrenergic nuclei in the brain are seemingly minor. An extremely high dose of 6-OHDOPA produces lethality, thus giving limitation to the practicality of 6-OHDOPA for a variety of studies.

6-OHDOPA was subsequently found to be an excitotoxin at non-NMDA (N-methyl-D-aspartate) receptors, likely because of it spontaneous generation of 6-OHDOPA-p-quinone, dopachrome, and dopaminechrome. As such, 6-OHDOPA is more excitotoxic than the endogenous NMDA receptor agonist glutamate. This action of 6-OHDOPA has the potential of producing an adverse spectrum of action when 6-OHDOPA is used as a selective noradrenergic neurotoxin. In summary, 6-OHDOPA has proven useful in defining elements of noradrenergic neuronal neurotoxicity, and for uncovering the sprouting potential of locus coeruleus neurons following perinatal damage.