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Pharmacological Reviews, Vol 26, 199-288, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics
1 Veterans Administration Hospital, New Orleans, Louisiana, and the Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland
From the previous discussions, it is apparent that 6-OHDA produces a relatively selective effect on sympathetic nerve terminals. The selectivity of this action appears to be related to its accumulation within noradrenergic neurons by uptake-1 transport mechanisms. Once inside the neuron, 6-OHDA is bound in a granular storage pool and can be released by nerve stimulation, thus acting as a false neurotransmitter. In sufficiently high amounts, apparently more related to the concentration in the cytoplasmic pool, 6-OHDA generates highly reactive products, suggested to be peroxides, superoxides, hydroxyindoles, and quinones. These products react nonspecifically with neuronal structures and eventually destroy the neuron. MAO appears to be important in the metabolism of the 6-OHDA molecule and this enzyme, as well as granule storage, may serve as protective mechanisms. The actual subcellular component most altered by 6-OHDA, and most involved with maintaining neuronal function, is not known. However, the endoplasmic reticulum, outer limiting membrane, nucleus, mitochondrion and other structures have been suggested as sites for the primary lesion, and 6-OHDA has been shown in vitro to uncouple oxidative phosphorylation in mitochondria. During the process of degeneration the nerves first lose their ability to conduct action potentials, NE stores become depleted and sympathomimetic responses may be observed. Uptake mechanisms become incapacitated and the nerve membrane ultimately is phagocytized, as evidenced by the intense neuroglia reaction. Accompanying the loss in the adrenergic nerve active amine uptake mechanism is the appearance of presynaptic supersensitivity at a host of sites. Development of postsynaptic supersensitivity has been suggested to occur with time in certain structures. In the peripheral nervous system the terminals regenerate, and it has been observed that functional activity is restored at early times, when the amine levels are still reduced and while the terminal network is far from being fully regenerated.
In the peripheral nervous system, 6-OHDA alters noradrenergic terminals to various degrees in different end organs. Time-course studies, following various routes of administration, have determined the threshold for terminal destruction in various organs of several species. In general, the increasing order for threshold of the destructive action of 6-OHDA in various end organs is cardiac ventricles 
salivary glands whole heart iris nictitating membrane spleen atria blood vessels vas deferens sympathetic ganglia adrenal glands. In regard to the adrenals it bears mentioning that they apparently are unaffected by direct 6-OHDA action, but respond to diminished sympathetic function by compensatorily increasing CA turnover. Terminals in all organs studied regenerate at a steady rate.
In the CNS of mature animals 6-OHDA produces marked alterations of both noradrenergic and dopaminergic neurons after injection into the parenchyma of the brain or into one of the brain cavities. Early studies showed that 6-OHDA in moderate doses could deplete the brain of NE in the absence of ultrastructural damage. Also, DA stores are initially increased after 6-OHDA and are depleted only as a consequence of damage to dopaminergic neurons. The regional effects of 6-OHDA on noradrenergic neurons in the brain vary according to the parameter under study. Different regional variations are found when either NE content, NE uptake or tyrosine hydroxylase activity is measured. The degeneration of the central noradrenergic neurons occurs in different phases, classified as primary and secondary degeneration. The primary phase is related to the direct destructive action of 6-OHDA on the neuron and occurs in about the first 48 hours after treatment. The secondary phase occurs over a period of weeks and appears to be the result of retrograde degenerative events subsequent to terminal or axonal damage.
Higher doses of 6-OHDA produce less of a specific effect, as is the case with any other pharmacological agent. Damage extends to noncatecholamine-containing neurons, and may even include non-neuronal cells. Possibly related to this type of unspecific damage is the observed depletion of 5-hydroxytryptamine in certain brain regions of different species. However, in reasonable amounts, 6-OHDA will destroy catecholaminergic neurons with a high degree of selectivity.
The histochemical method shows that 6-OHDA brings about alterations in the appearance of CA-containing nerves, similar to those observed after axonal section or ligation. Nerve terminal varicosities decrease in number, the nerve network stains less intensely, and finally, the number of terminal processes decreases. After a low dose of 6-OHDA the fluorescence intensity of nerves can be restored by subsequent treatment with a CA. However, after a high dose of 6-OHDA nerves are not unmasked by CA treatment, indicating that the initial depletion is followed by actual destruction. Correlations have been shown between histochemical alterations and reductions in endogenous CA levels, CA-uptake capacity, and endogenous DBH and T-OH activity. Electron microscopic studies have provided the ultimate confirmation of nerve terminal destruction. While the terminal network is undergoing these functional changes, the axonal processes become highly fluorescent, swollen and highly irregular in appearance. Evidence to date indicates that axoplasmic flow is impeded, so that NE, being transported down the axon, accumulates in a retrograde manner. The above alterations are seen in both noradrenergic and dopaminergic neurons.
In newborn mice and rats, 6-OHDA causes extensive damage of sympathetic postganglionic neurons, and the destructive lesion includes the entire neuron. Ganglia at prevertebral and paravertebral sites are destroyed and subsequent development is impaired throughout adulthood. As a consequence, numerous end organs normally innervated by sympathetic fibers, show a reduction of NE content due to the loss of the nerve network. In addition, central noradrenergic neurons are damaged, since 6-OHDA has the capacty of passing through the unfully-developed blood-brain barrier of the neonates. The pattern of this chemical lesion is different from that observed in mature animals.
Numerous behavioral parameters are altered by 6-OHDA. Initial behavioral changes are likely to result from NE or DA release from central CA-containing neurons after treatment with 6-OHDA, while more permanent alterations appear to be a better reflection of central neuronal destruction. Immediately after injection 6-OHDA decreases food and water consumption, lowers body temperature, and decreases locomotion More permanent effects are manifested by altered sleep patterns, increased irritability and aggression, and altered operant activity. Numerous studies have been performed to characterize the observed alterations to a specific region in the brain and also to the specific neurohumor involved.
Studies with 6-OHDOPA indicate that it is metabolically decarboxylated to 6-OHDA, which then destroys CA-containing neurons. It appears to be useful for selective destruction of noradrenergic neurons. One distinct advantage of 6-OHDOPA is its ability to cross the blood-brain barrier, so that both central and peripheral noradrenergic neurons may be destroyed after a single dose. Although 6-OHDOPA is far less potent than 6-OHDA in mature animals, the central neurotoxic actions in neonates are quite similar. However, unlike 6-OHDA, 6-OHDOPA does not appear to produce permanent alterations of all adrenergic neurons. Thus, as the animals develop one may be able to study the effects of centrally impaired noradrenergic development in the absence of peripheral effects. The limited studies to date indicate that 6-OHDOPA produces alterations in behavior that are similar to those produced by 6-OHDA.
Studies with 6-OHDA have illustrated the utility of this compound in investigating the function of both noradrenergic and dopaminergic neurons. Much has been learned about basic functional processes, such as uptake and storage mechanisms, axoplasmic transport, and the influence of central regulation of ongoing noradrenergic nerve development and function. It is now more meaningful to attempt to characterize the role of noradrenergic and dopaminergic neurons in different types of behavior. The search for other neurotoxic agents continues and perhaps others will be found with more desirable actions. However, the studies with 6-OHDA have provided new insights into innumerable areas of neuroscience.
Note:
The excellent secretarial assistance of Ms. Rene Atkinson and Ms. Lana Robinson during the preparation of this review is greatly acknowledged.
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