Biomedical subjects

M Menaker

Publications and source records attributed to M Menaker.

At least 73 records · Page 4Linked to original sources

PubMed1989

GABA regulation of circadian responses to light. I. Involvement of GABAA-benzodiazepine and GABAB receptors.

Light-induced phase shifts of the circadian locomotor rhythm of hamsters can be blocked by agents that alter GABA neurotransmission. The GABA antagonist bicuculline blocks phase delays induced by light and the benzodiazepine diazepam, which can potentiate GABA activity, blocks light-induced phase advances. In the experiments reported here, we found that the bicuculline blockade of phase delays was reduced by agents that mimic or potentiate GABA activity. Conversely, the diazepam blockade of phase advances was reduced by both competitive and noncompetitive antagonists of GABA. This indicates that the GABA-benzodiazepine receptor-ionophore complex is the most likely site of action for the effects of these drugs on circadian rhythms. However, competitive GABA agonists did not mimic the blocking effects of benzodiazepines, nor did the antagonist picrotoxin mimic the blocking effect of bicuculline. Therefore, the classic action of GABA, increased chloride conductance, may not be the effector mechanism in this case. We also found that the GABAB agonist baclofen blocked both phase advances and delays and that the blockade of advances was reversed by the antagonist delta-aminovaleric acid. Taken together, these results indicate that GABA is involved in the regulation of circadian responses to light and that the regulation is mediated by both GABAA and GABAB receptors.

Amino Acids↗

PubMed1988

A mutation of the circadian system in golden hamsters.

A mutation has been found that dramatically shortens the period of the circadian locomotor rhythm of golden hamsters. The pattern of inheritance of this mutation suggests that it occurred at a single, autosomal locus (tau). Wild-type animals have rhythms with free-running periods averaging about 24 hours; animals heterozygous for the mutation have periods of about 22 hours, whereas homozygous animals have rhythms with periods close to 20 hours. Animals that carry the mutant alleles exhibit abnormal entrainment to 24-hour light:dark cycles or are unable to entrain.

Activity Cycles↗

PubMed1988

Dose-response relationship between light irradiance and the suppression of plasma melatonin in human volunteers.

This study tested the capacity of different irradiances of monochromatic light to reduce plasma melatonin in normal humans. Six healthy male volunteers, 24-34 years old, were exposed to 0.01, 0.3, 1.6, 5, or 13 microW/cm2 of 509 nm monochromatic light for 1 h during the night on separate occasions. Light irradiance depressed plasma melatonin in a dose-response pattern. The data indicate that the mean threshold irradiance for suppressing melatonin is between 1.6 and 5 microW/cm2. Individual variations in threshold responses to monochromatic light were observed among the volunteers.

Adult↗

PubMed1987

Pineal indole metabolism in the mouse.

The activity of two pineal enzymes serotonin N-acetyltransferase (SNAT) and hydroxyindole-O-methyltransferase, (HIOMT) and the pineal content of serotonin (5-HT) and N-acetylserotonin (NAS) were measured in several strains of mice (Mus domesticus) in order to compare melatonin synthetic pathways among them. Of the strains we examined, C57BL/6J, AKR/J, BALB/c, NZB/BLNJ and wild mice, only wild mice synthesize pineal melatonin. Wild mice had high activity of both SNAT and HIOMT; NZB had SNAT activity but did not have HIOMT; the three other strains had neither SNAT nor HIOMT; the activity of SNAT in wild mice showed a clear daily rhythm but HIOMT activity did not show any significant daily changes. The pineal content of 5-HT in wild and NZB mice was higher during the day than during the night, however in C57BL and AKR, 5-HT levels were higher during the night than during the day. As expected NAS was found in wild and NZB mice.

Acetylserotonin O-Methyltransferase↗

PubMed1987

Kynurenic acid blocks suprachiasmatic nucleus responses to optic nerve stimulation.

An in vitro slice preparation of the mouse hypothalamus was used to determine the effects of pharmacological agents on the field potentials that are evoked in the suprachiasmatic nucleus (SCN) by stimulation of the optic nerve. Postsynaptic components of these responses were identified by lowering the concentration of calcium in the superfusate. Bath application of kynurenate, an antagonist of excitatory amino acid neurotransmission, reversibly blocked postsynaptic responses in the SCN. The evoked responses in the SCN were not affected by the acetylcholinergic agents (+)-tubocurarine, scopolamine, physostigmine, or carbachol. These results suggest that excitatory amino acid receptors mediate responses of SCN neurons to retinal input, but do not support a role for acetylcholine.

Animals↗

PubMed1987

Activity and reproductive state in the hamster: independent control by social stimuli and a circadian pacemaker.

Entrainment of circadian rhythms by social communication between male and female Syrian hamsters (Mesocricetus auratus) was tested by recording the wheel-running activity of pairs kept in the same cage but separated by a wire mesh barrier. Before pairing, males and females were synchronized to light/dark cycles that were 180 degrees out of phase, and at the time of pairing the hamsters were placed into constant darkness (DD). The activity rhythms of males and females housed in a cage alone (isolated) were also recorded. The freerunning periods of paired and isolated hamsters were not different over six weeks in DD, and no phase-shifts of the paired animals' rhythms were seen, indicating that the close proximity of a hamster of the opposite sex had no effect on the timing of the other's activity/rest rhythm. This was not due to a lack of communication between the paired males and females. Males showed four-day cycles in the amount and distribution of activity which corresponded to the estrous cycle of the female, and regression of the reproductive system which occurred in the isolated hamsters was delayed in both the paired males and females. Despite the fact that locomotor activity and reproduction are each regulated in part by a circadian pacemaker, social stimuli can affect both of these without influencing the circadian pacemaker that underlies the activity/rest rhythm.

Animals↗

PubMed1987

The intergeniculate leaflet partially mediates effects of light on circadian rhythms.

Photic signals affect circadian activity rhythms by both phasic and tonic mechanisms that modulate pacemaker phase and period. In mammals, the effects of light on circadian activity are mediated by the retina, which communicates with the suprahiasmatic nucleus (SCN) by two different anatomical routes: the retino-hypothalamic tract (RHT), originating in the retina, and the geniculo-hypothalamic tract (GHT), arising from a retino-recipient nucleus, the intergeniculate leaflet (IGL). We assessed the roles of these two afferent systems in mediating phasic and tonic effects of light on circadian activity in IGL-lesioned animals. Destruction of the IGL significantly affected phase shifts produced by brief light pulses (phasic effect) and modified the change in period (tau) of the free-running activity rhythm produced by changing the level of constant light (LL) (tonic effect). Phase advances produced by brief light pulses were decreased in amplitude while phase delays were increased in IGL-lesioned animals as compared to controls. The free-running period in constant dark (tau DD) of IGL-lesioned animals was greater than tau DD of controls, and the lengthening of tau normally produced by LL was not observed or was greatly reduced in IGL-lesioned animals. Entrainment to light-dark cycles was unaffected by the lesions, as were other aspects of the circadian activity rhythm that normally change in response to LL (e.g., activity-rest ratio, total activity, splitting). Our data support the interpretation that the IGL plays a significant role in relaying information regarding illumination intensity to the SCN.

Animals↗

PubMed1986

Dynamics of noradrenergic circadian input to the chicken pineal gland.

To analyze the dynamics of sympathetic input to the chicken pineal the concentrations of catecholamines, indoleamines and some of their metabolites were determined by high performance liquid chromatography with electrochemical detection (HPLC-EC) in the pineal glands of young chickens killed at different times of day. Rhythmic variations over 24 h were observed in tissue levels of dopamine (DA), 5-hydroxytryptamine (5-HT), N-acetylserotonin (NAS) and 5-hydroxyindoleacetic acid (5-HIAA), while norepinephrine (NE) concentrations exhibited no significant change. DA content peaked 2 h after onset of darkness and NAS was detectable only during the night. A bimodal pattern of 5-HT and 5-HIAA levels was observed with peak tissue levels occurring at dawn and dusk. To determine the possible differential effects of light on these biogenic amines, birds were sacrificed at midday, midnight and at midnight following a 1 h exposure to light, and their pineals processed for HPLC-EC. NE, DA and 5-HT levels were similar at midday and midnight, while 5-HIAA and NAS were elevated during the night. Midnight illumination decreased NE and NAS levels, increased 5-HT and 5-HIAA levels and had no effect on DA levels. Temporal variations in NE turnover were determined by pretreating young chickens with alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, and measuring the rates of decline in NE content over 2 h at midday and midnight in birds held on light cycles and at mid-subjective day in birds held in constant darkness (DD).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Effects of diazepam on circadian phase advances and delays.

Phase advances of hamster locomotor rhythms, which normally can be induced by light pulses in the late subjective night, were blocked in a dose-dependent manner by the benzodiazepine, diazepam. Light-induced phase delays were unaffected at doses that significantly blocked phase advances. Diazepam caused small phase delays of the free-running rhythm when given without a light pulse at either phase advance or phase delay time points. These results are discussed with regard to the possibility that different neurochemical mechanisms are required to process light-induced phase advances and delays and that GABA neurotransmission may be involved in the modulation of light input to the clock.

Animals↗

PubMed1986

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.

Animals↗

PubMed1986

Melatonin-induced increases in serotonin concentrations in specific regions of the chicken brain.

Day-night differences in the concentrations of melatonin and serotonin (5HT) were measured in several regions of the chicken brain, pineal gland and serum. Melatonin concentrations are higher at midnight than at midday in 8 of the 10 tissues studied although the amplitudes of these rhythms varied greatly. Day-night differences in the pineal, hypothalamus, thalamus, retina and pons-midbrain regions had the highest amplitudes. 5HT concentrations were rhythmic in only 3 of the tissues studied: the hypothalamus, thalamus and retina. These were also the areas of highest 5HT concentration. Exogenous melatonin, injected at midday, was taken up with similar patterns; the pineal, hypothalamus, thalamus and pons-midbrain contained more melatonin 20 min after injection than did other tissues. The rate of decline of melatonin concentration varied little among all tissues studied, suggesting that the differences among tissue concentrations were due to selective uptake mechanisms rather than specialized degradation pathways. The effects of exogenous melatonin on 5HT concentration were restricted to hypothalamus, thalamus, pons-midbrain, retina and pineal. No effect was seen in cerebellum, optic tectum, neostriatum, hippocampus and medulla oblongata. Together, these data strongly suggest that pineal (and exogenous) melatonin is selectively taken up primarily by three brain regions, hypothalamus, thalamus and pons-midbrain, in which it produces increases in 5HT concentrations. Regional selectivity of uptake may be the mechanism by means of which the effects of melatonin on 5HT-mediated function are restricted to specific brain areas.

Animals↗

PubMed1985

Bicuculline blocks circadian phase delays but not advances.

Phase delays of hamster locomotor rhythms, which normally can be produced by light pulses given in the early subjective night, were blocked by bicuculline, a selective antagonist of gamma-aminobutyric acid (GABA) activity. Phase advances induced by light pulses given in the late subjective night were unaffected by bicuculline. This suggests that GABA may be involved in the mediation of some, but not all, light input to the mammalian circadian system. Furthermore, it raises the possibility that light input may be mediated at different circadian time points by functionally separate pathways.

Animals↗

PubMed1985

Eyes--the second (and third) pineal glands?

The pineal gland, the retinas and perhaps other tissues as well may in some species produce melatonin that appears in significant quantities in the circulation. In at least one species, Japanese quail, the circadian rhythm in the levels of circulating melatonin reflects contributions from both the pineal and the retinas; in other species circulating melatonin may come exclusively from the pineal or perhaps only from the eyes. Comparative behavioural and physiological data from several bird and lizard species indicate that retinas and pineal glands fulfil similar endocrine roles. Current evidence suggests that in iguanid lizards either retinas or pineal glands, but not both in the same species, have important regulatory influences on circadian organization. This suggests that it should be relatively easy to influence the melatonin-forming ability of a tissue by natural selection, an interpretation bolstered by our finding that the ability to synthesize melatonin has been inadvertently eliminated in the pineal glands of laboratory mice, presumably by the selection involved in producing inbred strains. The genetics of melatonin synthesis in mice is briefly discussed.

Animals↗

PubMed1984

Is the avian circadian system a neuroendocrine loop?

Avian circadian organization is a result of a complex interaction of photoreceptive and oscillatory components. The known components include the pineal gland, the lateral eyes, the suprachiasmatic nuclei (SCN), and extraocular brain photoreceptors. The pathways by which these components integrate circadian rhythmicity suggest a neuroendocrine loop in which the SCN inhibits pineal and ocular oscillators during the course of subjective day via a multisynaptic neuronal pathway which includes the superior cervical ganglia (SCG). During the night, the pineal in turn inhibits SCN activity via its secretion of the hormone melatonin into the blood circulation. This neuroendocrine loop, it is proposed, synchronizes multiple oscillators within each component and maintains the stability and precision of the system.

Animals↗

PubMed1983

Daily rhythms of serotonin metabolism in the medial hypothalamus of the chicken: effects of pinealectomy and exogenous melatonin.

Indoleamine levels in punches of the medial hypothalamus containing the suprachiasmatic nuclei (SCN) of 4-week-old cockerels were determined by HPLC-EC. Melatonin levels in punches were determined by radioimmunoassay (RIA). Daily rhythms of serotonin (5-HT) and of its metabolite 5-hydroxy-3-indoleacetic acid (5-HIAA) were observed; levels were higher at midnight than at midday. A daily rhythm with the same phase in punch melatonin content was also observed. Pinealectomy at 1 week after hatching abolished the 5-HIAA and melatonin rhythm in 4-week-old birds but did not abolish the 5-HT rhythm. Injections of melatonin (0.5 mg/kg) increased 5-HT, 5-HIAA and melatonin levels in the hypothalamic punches. These results indicate that circulating melatonin of pineal origin may act to increase 5-HT turnover and/or release in the SCN. They suggest a link between the circadian secretion of pineal melatonin and the regulation of 5-HT projections to the hypothalamus from the raphe nuclei in the brainstem of the chicken. We have previously shown that the rhythmic secretion of melatonin by the pineal is influenced by oscillators in the brain via the superior cervical ganglia. The results reported here indicate that melatonin in turn may regulate brain oscillators, suggesting a neuroendocrine loop within the avian circadian system.

Animals↗

PubMed1983

Sympathetic regulation of chicken pineal rhythms.

Adult hens were chronically cannulated and held in light-dark (LD) 12:12 h lighting regimes or in constant darknesS (DD). Periodic blood sampling for 5-9 days revealed circadian rhythms in plasma melatonin titres. Superior cervical ganglionectomy (SCG-X) performed 1 week after hatching had little or no effect on these rhythms in LD, but unlike normals. SCG-X birds did not sustain persistent rhythms in DD. In SCG-X birds, norepinephrine (NE) infusion for 12 h of each 24 h in DD significantly reduced plasma melatonin titres during the infusion and re-established a rhythm. After each experiment, hens were killed, their pineals were removed and assayed by HPLC-EC for NE, dopamine (DA), serotonin (5-HT) and 5-hydroxy-3-indole-acetic acid (5-HIAA). SCG-X resulted in a 90% depletion of pineal NE: DA content was reduced to undetectable levels. Pineal 5-HT and 5-HIAA were also reduced by SCG-X. The chicken pineal contains circadian oscillators which persist in vitro8.19.29. The results reported here suggest that noradrenergic fibres from the SCG regulate the pineal's inherent rhythmicity. NE normally released from sympathetic terminals during the bird's day may synchronize oscillators within the pineal by inhibiting melatonin synthesis.

Animals↗

PubMed1983

Light-induced decrease of serotonin N-acetyltransferase activity and melatonin in the chicken pineal gland and retina.

In the pineal gland and retina of chickens, light exposure at night when serotonin N-acetyltransferase (NAT) activity levels are high causes a 4--5-fold decrease in NAT activity. The t1/2 of NAT inactivation is 10 min and the kinetics of inactivation are similar in the pineal gland and retina. A brief pulse of light can initiate the process of NAT inactivation which continues in the dark for 30 min before a partial recovery of NAT activity occurs. In blinded chicks, there is less inactivation of pineal NAT by light than in intact chicks, indicating that the eyes are involved in the pineal's response to light. In chicks that have had their superior cervical ganglia removed inactivation of pineal NAT by light is intermediate between that of intact and blind chicks, indicating that ganglionectomy does not completely mimic the effects of blinding. The pineal gland itself is light-sensitive in culture. Light causes a 4--5-fold decrease in NAT activity in static organ culture, and inhibits melatonin release in flow-through organ culture. Drugs that increase cyclic nucleotide levels in cells (cholera toxin, RO 20-1724, monobutyryl cyclic AMP, monobutyryl cyclic GMP) block the NAT decrease by light, whereas high potassium or EGTA do not block this light-induced NAT inactivation.

Acetyltransferases↗

PubMed1983

Temperature-compensated circadian clock in the pineal of Anolis.

The pineal organ of the lizard Anolis carolinensis can be maintained for up to 10 days in superfused organ culture. During this time it synthesizes and releases melatonin into the medium flowing slowly over it. Collection of timed aliquots of medium and subsequent analysis for melatonin by radioimmunoassay reveal circadian rhythms of melatonin output by the isolated pineal. These rhythms persist for many cycles in constant darkness and at several constant ambient temperatures ranging from 22 to 37 degrees C. The period of the rhythm is temperature compensated (Q10 approximately equal to 1.14) and the rhythm is synchronized by light-dark cycles imposed on the cultured gland. This isolated vertebrate organ displays the three major properties of circadian systems and must therefore contain one or more circadian oscillators.

Animals↗