Seasonal affective disorder (SAD) is a syndrome characterized by recurrent depressions that occur annually at the same time each year. We describe 29 patients with SAD; most of them had a bipolar affective disorder, especially bipolar II, and their depressions were generally characterized by hypersomnia, overeating, and carbohydrate craving and seemed to respond to changes in climate and latitude. Sleep recordings in nine depressed patients confirmed the presence of hypersomnia and showed increased sleep latency and reduced slow-wave (delta) sleep. Preliminary studies in 11 patients suggest that extending the photoperiod with bright artificial light has an antidepressant effect.

Seasonal Affective Disorder: A Description of the Syndrome and Preliminary Findings With Light Therapy

A syndrome similar to idiopathic parkinsonism developed after intravenous self-administration of an illicit drug preparation in which N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) might have been responsible for the toxicity. In the present study we show that intravenous administration of NMPTP to the rhesus monkey produces a disorder like parkinsonism (akinesia, rigidity, postural tremor, flexed posture, eyelid closure, drooling) that is reversed by the administration of L-dopa. NMPTP treatment decreases the release of dopamine and dopamine accumulates in swollen, distorted axons in the nigrostriatal pathway just above the substantia nigra, followed by severe nerve cell loss in the pars compacta of the substantia nigra and a marked reduction in the dopamine content of the striatum. The pathological and biochemical changes produced by NMPTP are similar to the well-established changes in patients with parkinsonism. Thus, the NMPTP-treated monkey provides a model that can be used to examine mechanisms and explore therapies of parkinsonism.

https://www.pnas.org/content/pnas/80/14/4546.full.pdf

A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

I Introduction UNTIL 35 yr ago, most scientists did not take research on the pineal gland seriously The decade beginning in 1956, however, provided several discoveries that laid the foundation for what has become a very active area of investigation These important early observations included the findings that, 1), the physiological activity of the pineal is influenced by the photoperiodic environment (1–5); 2), the gland contains a substance, N-acetyl-5-methoxytryptamine or melatonin, which has obvious endocrine capabilities (6, 7); 3), the function of the reproductive system in photoperiodically dependent rodents is inextricably linked to the physiology of the pineal gland (5, 8, 9); 4), the sympathetic innervation to the pineal is required for the gland to maintain its biosynthetic and endocrine activities (10, 11); and 5), the pineal gland can be rapidly removed from rodents with minimal damage to adjacent neural structures using a specially designed trephine (12) Since the mid 1960s, research on t

Pineal Melatonin: Cell Biology of Its Synthesis and of Its Physiological Interactions*

Bright artificial light suppressed nocturnal secretion of melatonin in six normal human subjects. Room light of less intensity, which is sufficient to suppress melatonin secretion in other mammals, failed to do so in humans. In contrast to the results of previous experiments in which ordinary room light was used, these findings establish that the human response to light is qualitatively similar to that of other mammals.

https://science.sciencemag.org/content/sci/210/4475/1267.full.pdf

Light Suppresses Melatonin Secretion in Humans

The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects' pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

https://www.jneurosci.org/content/jneuro/21/16/6405.full.pdf

Action Spectrum for Melatonin Regulation in Humans: Evidence for a Novel Circadian Photoreceptor

Three techniques have been used to measure human plasma melatonin: bioassay, radioimmunoassay, and gas chromatography--mass spectrometry (GC-MS). GC-MS is theoretically capable of the greatest specificity, but in general suffers from insufficient sensitivity. Negative chemical ionization, a new technique, provides a 150-fold increase in GC-MS sensitivity for electron-capturing compounds. Negative chemical ionization GC-MS permits routine measurement in human plasma of melatonin at a concentration as low as 1 picogram per milliliter.

https://science.sciencemag.org/content/sci/201/4357/741.full.pdf

Analysis of melatonin in human plasma by gas chromatography negative chemical ionization mass spectrometry

Using gas chromatography-negative ionization mass spectrometry, plasma melatonin levels in pinealectomized and sham-operated rats were assessed. The pinealectomized rats consistently demonstrated an absence of plasma melatonin while the intact animals showed detectable amounts. This suggests that although melatonin may be formed in tissues other than the pineal gland, the contribution to plasma is of pineal origin. Thus, plasma melatonin levels can be used as a marker of circadian melatonin secretion by the pineal gland and of its beta-adrenergic regulation.

Pinealectomy abolishes plasma melatonin in the rat

L-Kynurenine and quinolinic acid are neuroactive L-tryptophan-kynurenine pathway metabolites of potential importance in pathogenesis and treatment of neurologic disease. To identify precursors of these metabolites in brain, [(2)H(3) ]-L-kynurenine was infused subcutaneously by osmotic pump into three groups of gerbils: controls, CNS-localized immune-activated, and systemically immune-activated. The specific activity of L-kynurenine and quinolinate in blood, brain and systemic tissues at equilibrium was then quantified by mass spectrometry and the results applied to a model of metabolism to differentiate the relative contributions of various metabolic precursors. In control gerbils, 22% of L-kynurenine in brain was derived via local synthesis from L-tryptophan/formylkynurenine versus 78% from L-kynurenine from blood. Quinolinate in brain was derived from several sources, including: local tissue L-tryptophan/formylkynurenine (10%), blood L-kynurenine (35%), blood 3-hydroxykynurenine/3-hydroxyanthranilate (7%), and blood quinolinate (48%). After systemic immune-activation, however, L-kynurenine in brain was derived exclusively from blood, whereas quinolinate in brain was derived from three sources: blood L-kynurenine (52%), blood 3-hydroxykynurenine or 3-hydroxyanthranilate (8%), and blood quinolinate (40%). During CNS-localized immune activation, > 98% of both L-kynurenine and quinolinate were derived via local synthesis in brain. Thus, immune activation and its site determine the sources from which L-kynurenine and quinolinate are synthesized in brain. Successful therapeutic modulation of their concentrations must take into account the metabolic and compartment sources.

Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain

• The effects of antidepressant treatment on noradrenergic function were studied in 27 patients with a major affective disorder. Twenty-four-hour urinary excretion of 6-hydroxymelatonin and "whole-body norepinephrine (NE) turnover," ie, 24-hour urinary output of NE and its major metabolites 3-methoxy-4-hydroxyphenylglycol, vanillylmandelic acid, and normetanephrine, were measured before and after treatment with the tricyclic desipramine hydrochloride, the aminoketone bupropion hydrochloride, the nonselective monoamine oxidase (MAO) inhibitor tranylcypromine sulfate, and the specific MAO type A inhibitor clorgiline. 6-Hydroxymelatonin excretion increased following antidepressant treatment, while at the same time whole-body NE turnover was reduced. These findings support the hypothesis that antidepressant therapy increases noradrenergic "efficiency," in that functional output, as measured by 6-hydroxymelatonin, is maintained while total NE production is decreased.

S. P. Markey

Papers

Light Suppresses Melatonin Secretion in Humans

Analysis of melatonin in human plasma by gas chromatography negative chemical ionization mass spectrometry

Pinealectomy abolishes plasma melatonin in the rat

Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain

Antidepressants reduce whole-body norepinephrine turnover while enhancing 6-hydroxymelatonin output.