Biological interest in catecholamines, in particular epinephrine, dates back to the final years of the nineteenth-century. Within one decade after Oliver and Schaefer in 1895 showed that an extract of the adrenal medulla produced a marked increase in blood pressure, its active constituent epinephrine (adrenaline) was isolated, purified, and synthesized. Epinephrine was the first hormone isolated in crystalline form. Elliott's studies in 1905 with epinephrine are of greater importance from our perspective. His results provided an important clue in the development of the nascent concept that chemicals rather than electrogenic forces were responsible for carrying messages from nerve endings to effector tissues. Direct proof of chemically-mediated neurotransmission came in 1921 with Loewi's brilliant, but simple, experiments demonstrating the release of Vagustuff (later shown to be acetylcholine) from the electrically-stimulated vagus nerve of a frog's heart .
During the 1920s and 30s, Cannon observed that the changes in blood pressure and heart rate produced by a chemical released after stimulation of sympathetic nerves, which he called "sympathin," were similar but differed somewhat from those changes produced by an injection of epinephrine. This discrepancy was clarified by von Euler in the 1946 when he discovered that norepinephrine, a biological precursor of epinephrine, was the neurotransmitter released from these nerve endings. Early research interest in norepinephrine (noradrenaline) focused upon its effects on peripheral tissues, with emphasis on the cardiovascular system, and its role as the primary sympathetic postganglionic neurotransmitter.
In the 1950s, the interest shifted to the central nervous system. Marthe Vogt found that norepinephrine was differentially distributed in different regions of the brain leading her suggestion that it might act as a central neurotransmitter. Using fluorescent techniques, Falck and Hillarp visualized noradrenergic pathways and identified the location of their cell bodies in the pons (locus ceruleus) and medulla, with their nerve terminals in the cerebral cortex, limbic system, and hypothalamus. In addition, ascending and descending noradrenergic fibers were found to pass through the medial forebrain bundle with their nerve fibers traveling to the cerebral cortex, hippocampus and cerebellum . Brodie and Shore postulated that norepinephrine was the primary neurotransmitter of sympathetic centers in the brain, and that the effects of a number of psychoactive drugs, including amphetamine, ephedrine, and mescaline, might result from their interaction with norepinephrine.
If biogenic amines were associated with normal brain function, might changes in their functional activity play a role in mental disease or other disfunctions of the central nervous system? The results of neuropharmacological studies in animals supported clinical observations that drug-induced depletion of brain norepinephrine with reserpine caused depression, while elevation of its levels at sympathetic synapses alleviated clinical depression or even elevated the mood. In his 1965 "catecholamine hypothesis of affective disorders," Schildkraut proposed that depression is associated with a decrease and mania an excess in the functional activity of norepinephrine at these synapses. This model provided a unified framework to explain the mechanisms of action of antidepressant and antimanic drugs. While elements of this hypothesis remain appealing four decades later, and norepinephrine is still thought to play a role in some depressive illnesses, significant inconsistencies and new research findings now place greater emphasis on serotoninergic involvement in depression and the use of selective serotonin reuptake inhibitors for its treatment .
In addition to mood disorders, norepinephrine has been implicated in mechanisms involved with arousal and sleep . Electrodes implanted in the locus ceruleus in animals show increased activity during periods of arousal, while the electrical activity in this area is absent during sleep. Sleep is not a uniform state but rather cycles at 90-minute intervals between periods of rapid-eye movements (REM), which is associated with dreaming, and non-REM sleep. Changes in the release of norepinephrine, serotonin, and acetylcholine are observed during and between these sleep phases. During deep sleep, norepinephrine levels decline and serotonin levels rise, while REM sleep is thought to be induced by the release of norepinephrine and acetylcholine .
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