METABOLISM OF NOREPINEPHRINE IN THE CENTRAL NERVOUS SYSTEM
Authors: JACQUES GLOWINSKI, ROSS J. BALDESSARINI
Journal: Pharmacological Reviews (1966)

In the past few years a great deal of information has accumulated about the distribution and metabolism of catecholamines in the central nervous system, owing largely to new experimental approaches. These studies promise to enrich our conception of the functional anatomy of the brain.

Norepinephrine is contained in complex systems of specific neurons and is highly localized at nerve terminals, largely within synaptic vesicles. The metabolism of norepinephrine in the brain is generally similar to that in the peripheral sympathetic system. In both systems, tyrosine is converted to norepinephrine intraneuronally, following the same enzymatic pathway. Intraneuronal oxidative deamination and extraneuronal O-methylation are important catabolic processes in both systems. As in the periphery, the processes of active uptake and storage are remarkably efficient and greatly facilitate the study of the metabolism of this amine since radioactive tracers are readily taken up and retained by norepinephrine neurons. Reuptake may be a major means of inactivating physiologically released norepinephrine. The amine is stored in central neurons in a protected and inactive form, which appears to be a reservoir for future functional needs. Since the disappearance of endogenously formed radioactive norepinephrine is multiphasic, and since drugs have a differential depleting action on subcellular fractions of norepinephrine, it appears to occur in the brain in more than one form, as in the periphery. Even among relatively homogeneous populations of sympathetic nerve endings in peripheral organs, it is difficult to correlate the functional compartmentalization of norepinephrine with its intracellular distribution. In the central nervous system, the apparent compartmentalization of norepinephrine may be due not only to different forms of its storage within individual nerve terminals, but also to metabolic or storage differences between cell bodies and terminals, or between groups of neurons which are heterogenous in size and distribution.

Norepinephrine fulfills several criteria of neurotransmitter. The amine is highly localized at nerve terminals in vesicles. It can be synthesized and stored locally, and very efficient mechanisms exist for its inactivation at synapses. In the peripheral sympathetic system, other fundamental criteria for chemical neurotransmission have been fulfilled. They include the release of norepinephrine by nerve stimulation and the ability of exogenous norepinephrine to mimic postsynaptic effects of sympathetic stimulation. In the brain, it has not yet been possible to demonstrate direct release of norepinephrine by neural activity in the intact brain, although indirect evidence for release has been obtained. In the central nervous system, postsynaptic effects are more difficult to study than at peripheral neuroeffector junctions. Although it has been possible to study the sensitivity of neurons to norepinephrine applied by microelectrophoresis, specific electrical criteria for postsynaptic responses produced uniquely by noradrenergic neurons have not been established. Norepinephrine has both excitatory and inhibitory effects in various areas of the central nervous system. This work has recently been reviewed elsewhere (266, 267).

It is difficult to relate the neurological effects of centrally active drugs to their neurochemical effects, or to explain the mechanisms of such drugs by isolated effects on individual groups of neurons. Chemical effects have usually been studied in acute experiments with relatively large doses of drugs, and they may not correspond to the chemical changes resulting from chronic treatment.

Despite these limitations, it is possible to make certain conclusions about the actions of several important pharmacological agents on norepinephrine metabolism. Several drugs induce striking changes in brain catecholamine concentrations. Several mechanisms may lead to accumulation or depletion of norepinephrine, and significant metabolic changes may occur even without appreciable changes in norepinephrine concentration. Several metabolic alterations may occur simultaneously and may induce secondary metabolic responses, such as changes in the rate of turnover. The net effect produced may be the result of complementary or antagonistic actions of the drug. From the present survey of drug interactions with central norepinephrine metabolism, it appears that compounds that decrease synthesis, alter or compete for storage sites, or block release, may decrease central neural activity, most likely by limiting the availability of norepinephrine at the synapse. In contrast, the administration of precursors of norepinephrine, or of drugs which activate release, inhibit reuptake or prevent enzymatic inactivation, is followed by a syndrome of central excitation, probably due to increased availability of norepinephrine at the synapse. These interpretations are complicated by the uncertainty about the role of norepinephrine as an excitatory or inhibitory transmitter in the brain. Even though the present conclusions seem rather naive, more sophisticated concepts are rapidly emerging in the relatively new field of biochemical neuropharmacology.