Pineal gland: 24-hour rhythm in norepinephrine turnover

There is a 24-hour rhythm in the turnover of norepinephrine in sympathetic nerves innervating the pineal gland. This rhythm persists in blinded animals but is suppressed in normnal rats by light. The rhythm in norepinephrine turnover generates the rhythums in pineal indoleamines and N-acetyltransferase.     

Melatonin synthesis: adenosine 3',5'-monophosphate and norepinephrine stimulate N-acetyltransferase

Treatment of cultured rat pineal glands with norepinephrine or dibutyryl adenosine 3',5'-monophosphate causes a six- to tenfold stimulation of N-acetyltransferase. This enzyme converts serotonin to N-acetylserotonin, the immediate precursor of melatonin. The increased synthesis of melatonin caused by norepinephrine treatment appears to be the result of stimulation of N-acetyltransferase by an adenosine 3',5'-monophosphate mechanism.     

Pineal N-acetyltransferase activity: effect of sympathetic stimulation

Stimulation of preganglionic sympathetic fibers to the superior cervical ganglia elevates the activity of pineal N-acetyltransferase. After the stimulation-induced rise in enzyme activity, a return toward baseline levels occurs whether or not nerve stimulation is continued. The ability of pineal N-acetyltransferase activity to fall in the presence of stimulation may account for the persistence of its rhythm in blinded animals.     

Rapid light-induced decrease in pineal serotonin N-acetyltransferase activity

Light acting by way of the eye causes the dark-induced activity of serotonin N-acetyltransferase in the pineal gland of the rat to decrease with a halving time of about 3 minutes. This effect, which is one of the more rapid physiological changes known to occur in the activity of any enzyme that metabolizes biogenic amines, appears to explain the rapid increase in the concentration of pineal serotonin that is caused by light exposure at night.     

Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the brain

The anxiety-reducing effects of minor tranquilizers in the rat conflict test were mimicked by serotonin antagonists and by p-chlorophenylalanine, an inhibitor of serotonin synthesis; the depressant effects of the minor tranquilizers were mimicked by norepinephrine antagonists. Intraventricular injections of serotonin led to a suppression of behavior, and also antagonized the anxiety-reducing action of benzodiazeprines. Intraventricular injections of norepinephrine led to a release of punished behavior from suppression, and also antagonized the depressant action of benzodiazepines. The anxiety-reducing activity, and the decrease in serotonin turnover induced by benzodiazepines, were maintained over repeated doses, whereas depressant activity, and the decrease induced in norepinephrine turnover, both rapidly underwent tolerance. Tranquilizers may exert their anxiety-reducing effects by a reduction of serotonin activity in a behaviorally suppressive punishment system, and they may exert their depressant effects by a reduction of norepinephrine activity in a behaviorally facilitatory reward system.     

A strong influence of serotonin axons on beta-adrenergic receptors in rat brain

The role of serotonin axons in modulating the norepinephrine neurotransmission system in rat brain was investigated. Selective lesions of the forebrain serotonergic system were made by injecting 5,7-dihydroxytryptamine into the midbrain raphe nuclei. Four to six weeks after the lesion, the uptake of 3H-labeled serotonin in the frontal cortex and the hippocampus was reduced by more than 90 percent, while neither the uptake of 3H-labeled norepinephrine nor the content of norepinephrine was affected in either tissue. The number of beta-adrenergic receptors, as measured by radioligand binding with 3H-labeled dihydroalprenolol, was increased in the frontal cortex and hippocampus of rats with lesions. Similarly, specific lesions of central serotonin axons produced by systemically administered p-chloramphetamine resulted in an increase in the binding of 3H-labeled dihydroalprenolol to beta-adrenergic receptors and in the production of adenosine 3',5'-monophosphate in response to isoproterenol. These results indicate that serotonin axons may regulate beta-adrenergic receptor number and function in brain.     

Is reserpine tranquilization linked to change in brain serotonin or brain norepinephrine?

Reserpine, when administered to animals stressed by exposure to cold, does not induce sedation or appreciably lower brain serotonin, but markedly lowers brain norepinephrine. Reserpine in cold-exposed hypophysectomized rats elicits sedation and releases both amines equally. The results support the view that the tranquilizing action of reserpine is not related to brain norepinephrine loss but rather to change in the level of brain serotonin.     

Vascular smooth muscle reactivity in normotensive and hypertensive rats

Aortic strips from spontaneously hypertensive rats were less responsive than normal animals to the contractile effects of norepinephrine, serotonin, and potassium chloride but more reactive to the relaxant effects of the stimulant of beta receptors, isoproterenol. Thus, hypertension is not the result of an absence of beta receptor or a hypersensitivity of the vascular smooth muscle.     

Harderian gland: an extraretinal photoreceptor influencing the pineal gland in neonatal rats?

The circadian rhythm of pineal serotonin and the influence of light on that rhythm have been confirmed. Removal of the Harderian gland abolishes the response to light in blinded animals, which suggests that this gland may act as the extraretinal transducer involved in the persistence of the pineal rhythm in blinded suckling rats.     

L-dopa: effect on concentrations of dopamine, norepinephrine, and serotonin in brains of mice

Large doses of L-dopa given to mice produced marked increases in brain dopamine, no change in norepinephrine, and a remarkable decrease in brain serotonin. This reduction apparently results from a release or displacement, or both, of serotonin from its storage sites.     

Circadian rhythm of serotonin in the pineal body of immunosympathectomized immature rats

In the pineal body of the immature rat the circadian rhythm of serotonin persists when sympathetic innervation is abolished by the administration of nerve growth factor antiserum. This rhythm is regulated by a mechanism that does not involve the sympathetic innervation and is, therefore, fundamentally different from that in the adult.     

Cyclic adenosine monophosphate: stimulation of melatonin and serotonin synthesis in cultured rat pineals

Dibutyryl cyclic adenosine monophosphate, like norepinephrine, stimulates the synthesis of labeled melatonin and serotonin from tryptophan labeled with carbon-14 by rat pineals in organ culture. Unlike norepinephrine, dibutyryl cyclic adenosine monophosphate does not enhance the accumulation of labeled tryptophan or protein within the pineal. These findings are compatible with the hypothesis that cyclic adenosine monophosphate mediates some, but not all, of the effects of norepinephrine.     

Genetic control of melatonin synthesis in the pineal gland of the mouse

Pineal melatonin may play an important role in regulation of vertebrate circadian rhythms and in human affective disorders. In some mammals, such as hamsters and sheep, melatonin is involved in photoperiodic time measurement and in control of reproduction. Although wild mice (Mus domesticus) and some wild-derived inbred strains of mice have melatonin in their pineal glands, several inbred strains of laboratory mice (for example, C57BL/6J) were found not to have detectable melatonin in their pineal glands. Genetic analysis suggests that melatonin deficiency in C57BL/6J mice results from mutations in two independently segregating, autosomal recessive genes. Synthesis of melatonin from serotonin in the pineal gland requires the enzymes N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT). Pineal glands from C57BL/6J mice have neither NAT nor HIOMT activity. These results suggest that the two genes involved in melatonin deficiency are responsible for the absence of normal NAT and HIOMT enzyme activity.     

Facilitation of brain self-stimulation by central administration of norepinephrine

Rats with electrodes implanted in the medial forebrain bundle stimulated their own brains at sharply reduced rates after systemic administration of disulfiram or intraventricular administration of diethyldithiocarbamate. Both drugs inhibit dopamine-beta-hydroxylase, the enzyme responsible for the final step in the biosynthesis of norepinephrine. The suppressed behavior was reinstated by intraventricular injections of 1-norepinephrine, but not by injection of its biologically inactive isomer, d-norepinephrine. Intraventricular administration of dopamine and serotonin did not restore self-stimulation. The rewarding effect of medial forebrain bundle stimulation may depend on the availability of norepinephrine as a transmitter, but not on dopamine or serotonin.     

Lesions of central norepinephrine terminals with 6-OH-dopamine: biochemistry and fine structure

Intracisternal injections of 6-hydroxydopamine produce rapid and long-lasting depletion of brain catecholamines without effects on serotonin concentrations. Depletion of norepinephrine is greatest in areas containing only nerve terminals and axons and least in areas containing monoamine cell bodies. The norepinephrine loss is accompanied by electron microscopic evidence of nerve terminal degeneration and decreased turnover. Dopamine loss is less marked and is not accompanied by degeneration or alteration of turnover rate.     

Behavioral response rates in pigeons: effect of alpha-methyl-m-tyrosine

An intramuscular injection of alpha-methyl-m-tyrosine ( 100 mg/ kg), which differentially depletes serotonin and norepinephrine in both brain and heart, was given to two groups of pigeons trained to peck at a key for food. The first group received an injection 12 hours before the daily session and showed no behavioral effect. Response rates of birds in the second group, which were injected 30 minutes after the start of the daily session, decreased and returned to normal within 9 hours after injection. Preliminary data on brain serotonin of pigeons indicate that the disruption of the behavior follows the same time course as the change in serotonin.     

Adenylate cyclase activation shifts the phase of a circadian pacemaker

Forskolin, a highly specific activator of adenylate cyclase, produced both delay and advance phase shifts of the circadian rhythm recorded from the isolated eye of the marine mollusk Aplysia. The phase dependence of the response to forskolin was identical to that with serotonin, which also stimulates adenylate cyclase in the eye. The ability of agents to activate adenylate cyclase in homogenates was correlated with their ability to shift the phase of the circadian oscillator. These results along with earlier findings show that adenosine 3',5'-monophosphate mediates the effect of serotonin on the rhythm and regulates the phase of the circadian pacemaker in the eye of Aplysia.     

Brain serotonin concentration: elevation following intraperitoneal administration of melatonin

The intraperitoneal administration of melatonin to rats caused an increase in brain serotonin concentration, especially in the midbrain. This effect could be demonstrated within 20 minutes of melatonin administration and was not associated with changes in norepinephrine concentration.     

Pharmacologic effects in man of a specific serotonin-reuptake inhibitor

Fluoxetine (Li-ly 110140) caused a 63 percent inhibition of [3H]serotonin uptake into platelets obtained from normal volunteers to whom the drug was administered daily for 7 days. This dose had no effect on the usual pressor response produced by injections of norepinephrine or tyramine.     

Alterations in the pattern of amine excretion in man produced by a monoamine oxidase inhibitor

The administration of monoamine oxidase inhibitors produces an increase in the urinary excretion of many amines for which efficient alternate routes of metabolism are not available. These include tryptamine, paratyramine, and a "metatyramine-like" substance. The inhibitors can therefore be used to detect previously unsuspected pathways of amino acid decarboxylation. The finding that the excretions of norepinephrine, epinephrine, 3,4-dihydroxyphenylethylamine, and possible serotonin are not appreciably affected are consistent with previous reports of the existence of alternative metabolic routes.