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Biomedical subjects

G Huether

Publications and source records attributed to G Huether.

At least 37 records · Page 2Linked to original sources
PubMed1998

Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions.

The fate and disposition of the melatonin released into the circulation is still poorly understood, and almost all current knowledge is derived from measurements made after a single and often a very large dose of labelled melatonin. In continuous infusion experiments in freely moving rats, we have recently demonstrated that considerable amounts of melatonin must be endogenously released in order to achieve and maintain approximately a 10-fold elevation of the low daytime plasma levels of this hormone. We have now applied this infusion paradigm to study the fate and tissue accumulation of [3H]-melatonin continuously infused under near physiological conditions into the jugular vein for a period of 2 hr. The retention of [3H]-melatonin and chloroform-insoluble [3H]-melatonin-metabolites was measured in almost all body tissues and their subcellular compartments immediately at the end of the infusion period and 6 hr later. At the end of the 2 hr infusion period, about 45% of the administered melatonin was recovered as water-soluble metabolites in the urine and about 20% in the small intestine. Some accumulation of [3H]-melatonin-derived water-soluble radioactivity was also noticed in the liver, colon, adrenals, and pituitary, as well as in the feces. The subcellular distribution of this radioactivity differed between tissues. During the period of 6 hr after the termination of infusion, a considerable amount of melatonin-derived radioactivity was found to become increasingly attached to the proteous interlayer of chloroform extracts of tissues and subcellular fractions, from where it could only be liberated by protease treatment.

Adrenal Glands↗
PubMed1998

Effect of continuous melatonin infusions on steady-state plasma melatonin levels in rats under near physiological conditions.

It was the aim of this study to measure the actual amount of melatonin required for elevating the circulating hormone from low daytime levels to the 10-fold higher nocturnal steady-state concentrations in rats. For this purpose, escalating doses of melatonin were continuously infused into the right jugular vein and blood samples were repeatedly drawn from the left jugular vein for a period of 2 hr in freely moving catheterized rats. In order to achieve an about 10-fold elevation of the plasma melatonin concentration, 500 ng melatonin/hr had to be infused, i.e., about 300 times the normal nocturnal melatonin content of the pineal. Infusions of up to 61 ng melatonin/hr (equivalent to the melatonin content of 40 pineals at darkness) failed to cause a significant rise of the low daytime steady-state concentrations in the blood. If the dose of 500 ng melatonin/h was infused at night, a less-pronounced rise of the blood levels was observed, as compared to that caused by the infusion of the same dose during daytime. No differences were found in the rate of metabolism between daytime and nighttime. The results of this study indicate 1) that the low basal concentrations of melatonin in the blood are not affected by an increased melatonin supply up to a certain critical threshold, 2) that the rat pineal gland would have to release all its melatonin content almost every 10 sec in order to sustain the elevated steady-state level of melatonin in the circulation during the dark period, and 3) that significant day/night differences exist in the disposition of circulating melatonin if administered in near physiological amounts and under near physiological conditions.

Animals↗
PubMed1997

Long-term food restriction down-regulates the density of serotonin transporters in the rat frontal cortex.

The influence of feeding rats only half the amount of their normal daily intake of a complete rat chow on the affinity and the density of serotonin (5-HT) transporters was measured in membrane preparations of the frontal cortex and the midbrain by a [3H]paroxetine binding assay. In young rats (10 weeks), a significant reduction of about 30% of the Bmax values of [3H]paroxetine binding occurred in the frontal cortex after 1 and 2 weeks of restricted food intake. No starvation-induced decline of the density of 5-HT transporters was seen in the midbrain. When older rats (50 weeks) were subjected to the same 50% reduction of daily food intake for 2 weeks, no such down-regulation of the density of cortical 5-HT transporters was observed. The affinity of the 5-HT transporters, as indicated by the unchanged Kd values of [3H]paroxetine binding, was not affected by semistarvation in both regions and at both ages. The observed decline of [3H]paroxetine binding sites in the frontal cortex of young adult rats is the first demonstration of long-term regulatory phenomena of brain 5-HT transporters triggered by a physiologic stimulus.

Aging↗
PubMed1997

Long-term modulation of presynaptic 5-HT-output: experimentally induced changes in cortical 5-HT-transporter density, tryptophan hydroxylase content and 5-HT innervation density.

Whereas experimentally induced long-term changes of postsynaptic mechanisms of 5-HT neurotransmission have been studied in great detail, much less is currently known about the effects of certain treatments on the presynaptic components governing the output of 5-HT in individual brain regions. This contribution summarizes the results of a series of experiments on the influence of different physiologic and pharmacologic manipulations on three different parameters of 5-HT presynapses, 5-HT transporter density, tryptophan hydroxylase content, and serotonin level in the rat frontal cortex. The combined measurement of several parameters of 5-HT presynapses allows to differentiate between treatments which exclusively affect the density of 5-HT transporters (long-term food restriction), which exclusively affect the level of tryptophan hydroxylase apoenzyme (imipramine treatment of olfactory bulbectomized rats) or which cause a parallel increase (bulbectomy, chronic administration of tranylcypramine to rats with chemical lesions of their cortical 5-HT innervation) or a parallel decrease (administration of p-chloroamphetamine) of both parameters, indicating treatment-induced changes in the density of 5-HT presynapses in the frontal cortex. Each of these changes may lead to an altered output of serotonergic afferences, and may therefore act to either potentiate or to attenuate the impact of serotonin-mediated effects on the activity of local networks located in a certain brain region.

Animals↗
PubMed1997

Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and its congeners.

The massive and prolonged stimulation of serotonin (5-HT)-release and the increased dopaminergic activity are responsible for the acute psychomimetic and psychostimulatory effects of 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy") and its congeners. In vulnerable subjects, at high doses or repeated use, and under certain unfavorable conditions (crowding, high ambient temperature), severe, in some cases fatal, averse systemic reactions (hyperthermia, serotonin-syndrome) may occur during the first few hours. Animal experiments revealed the existence of similar differences in vulnerability and similar dose- and context-related influences on a similar sequence of acute responses. The severity of these acute systemic responses is closely related to the severity of the long-term damage to 5-HT axon terminals caused by the administration of substituted amphetamines. Attempts to identify the mechanisms involved in this selective degeneration of 5-HT presynapses brought to light a multitude of different factors and conditions which either attenuate or potentiate the loss of 5-HT terminals caused by MDMA and related amphetamine derivatives. These puzzling observations suggest that the degeneration of 5-HT presynapses represents only the final step in a sequence of events which compromise the ability of 5-HT terminals to maintain their functional and structural integrity. Substituted amphetamines selectively tax energy metabolism in 5-HT presynapses through their ability to exchange with 5-HT and to dissipate transmembrane ion gradients. The active carrier systems in the vesicular and presynaptic membrane operate at a permanently activated state. The resulting energy deficit can no longer adequately restored by the 5-HT presynapses when their availability of substrates for ATP production is additionally reduced by the hyperthermic and other energy consuming reactions which are elicited by the systemic administration of substituted amphetamines. The exhaustion of energy in 5-HT nerve terminals compromised all energy-requiring endogenous mechanisms involved in the regulation of transmembrane-ion exchange, internal Ca(++)-homeostasis, prevention of oxidative stress, detoxification, and repair. Above a critical threshold the failure of these self-protective mechanisms will lead to the degeneration of the 5-HT axon terminals. Based on the role of 5-HT as a global modulatory transmitter-system involved in the stabilization and integration of impulse flow between distributed multifocal neuronal networks, the partial loss of 5-HT presynapses must be expected to impair the ability of these networks to maintain the integrity of signal flow pattern, and increase the likelihood of switching to unstable information processing. Behavioral responding may therefore become more dominated by activities generated in individual networks, and hitherto "buffered" personality traits and predisposition may become manifested as defined psychiatric syndromes in certain predisposed subjects.

Amphetamine-Related Disorders↗
PubMed1997

No evidence for a physiological coupling between melatonin and glucocorticoids.

Much has been speculated about the existence of a physiological coupling between melatonin and glucocorticoid secretion and about a possible anti-stress action of melatonin. We examined the relationship between melatonin and glucocorticoid secretion under close-to-physiological conditions, when the plasma concentration of either melatonin or glucocorticoids was elevated acutely or chronically in both rats and humans. Tryptophan administration caused a massive rise of plasma melatonin, but had no effect on corticosterone levels in rats or on cortisol levels in humans. The acute and long-lasting exposure of rats to uncontrollable stress resulted in a significant rise of adrenal corticosterone secretion, but had no effect on circulating melatonin levels. Orchectomy caused an initial increase in circulating corticosterone (when melatonin was unaffected) and a delayed rise in circulating melatonin (when corticosterone levels were normalized). In humans, no correlation was found between the nocturnal urinary excretion of melatonin and cortisol, either among healthy subjects, or among patients suffering from panic disorder (with an increased urinary excretion of cortisol) or among insomnia patients (with a high incidence of low melatonin secretion). Furthermore, no evidence was found for a suppressive action of melatonin on dexamethasone-mediated thymus regression in rats and on dexamethasone-mediated suppression of lymphocyte proliferation in vitro. Taken together, the results of this study provide no evidence for the existence of mutual influences between melatonin and glucocorticoid secretion, nor do they support the proposed attenuation of glucocorticoid-mediated effects on target cells or tissues by melatonin under physiological conditions.

Adult↗
PubMed1997

Influence of olfactory bulbectomy and subsequent imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: behavioural correlates.

1. Alterations of 5-hydroxytryptaminergic mechanisms are thought to play a special role in the pathogenesis of depression and antidepressant treatments are assumed to restore these changes. 2. We have used one of the most reliable models of depression, the olfactory bulbectomized rat to study the long term consequences of this manipulation and of subchronic imipramine treatment on two parameters of 5-hydroxytryptaminergic presynapses, 5-hydroxytryptamine (5-HT) transporter density and tryptophan hydroxylase apoenzyme concentration, in the frontal cortex as well as on active avoidance learning several weeks after bulbectomy. 3. The Bmax value of [3H]-paroxetine binding and the concentration of the 5-HT synthesizing enzyme were both significantly elevated in the frontal cortex of bulbectomized rats compared to sham-operated controls. 4. Imipramine treatment, either by daily injections or by subcutaneous implantation of slow release imipramine-containing polymers reduced the elevated tryptophan hydroxylase apoenzyme levels in the frontal cortex of bulbectomized, but not of sham-operated control rats and restored the deficient learning performance of bulbectomized rats. 5. Both effects were more pronounced after continuous drug administration by imipramine-releasing polymers compared to daily i.p. injections. 6. These findings indicate that bulbectomy leads to a compensatory 5-hydroxytryptaminergic hyperinnervation of the frontal cortex. Chronic antidepressant treatment seems to attenuate the increased output of the 5-hydroxytryptaminergic projections in the frontal cortex through the destabilization of the rate limiting enzyme of 5-HT synthesis of the 5-hydroxytryptaminergic nerve endings in this brain region.

Adrenergic Uptake Inhibitors↗
PubMed1997

Serotonin acts as a radical scavenger and is oxidized to a dimer during the respiratory burst of activated microglia.

Serotonin (5-HT) is known to be readily oxidized and to act as a scavenger of reactive oxygen species produced, e.g., in the presence of peroxidase and H2O2 or during the respiratory burst of phagocytes. One major oxidation product formed under these conditions, the 5-HT dimer 5,5'-dihydroxy-4,4'-bitryptamine (DHBT), was suggested to have neurotoxic properties and to contribute to neuronal damage in neurodegenerative disorders. It is shown in the present study that the luminol-enhanced chemiluminescence signal measured after stimulation of the respiratory burst activity of cultivated rat microglial cells by the addition of phorbol 12-myristate 13-acetate is suppressed by 5-HT in a dose-dependent manner. During this process, 5-HT is oxidized to DHBT. Neither the intraventricular injection of DHBT nor the addition of DHBT to cultured astrocytes, neurons, or PC-12 cells was found to cause measurable cytotoxic effects. It is concluded that extracellular 5-HT locally released from platelets and 5-HT nerve endings at sites of brain damage or inflammation, through its suppressant effect on the release of reactive oxygen species during the respiratory burst of activated microglia, may contribute to attenuate secondary tissue damage in the CNS.

Animals↗
PubMed1997

On the problems of switching from intravenous to oral administration in drug treatment of endogenous depression--a placebo-controlled double-blind trial with doxepin.

In the treatment of depressive disorders the onset of action can be accelerated if the antidepressant drug is initially administered by intravenous infusion. It is not clear whether this effect is due to pharmacological or to psychological effects of the infusion setting. The necessary switch to oral administration may be problematic. Uncontrolled observations indicate that it could be associated with a remarkable deterioration in the course of the disease. This randomized double-blind placebo-controlled study on doxepin is the first investigation of the effect of the switch from parenteral to oral administration on symptoms of endogenous depression. The hypothesis to be tested, that there is a significant worsening of treatment response during the switch, must be rejected on the basis of objective and subjective psychometric tests. There was in fact a continuous improvement. Precondition was a selection of patients with typical "endogenous" depressions and maintenance of at least constant plasma levels of the active antidepressants. In patients under the age of 65 years this can generally be achieved by switching in a ratio of 125 mg i.v. to 250 per os in the case of doxepin. Individual case studies indicated that a worsening in the patient's progress after switching was correlated with a decreasing plasma level of the active drug. Low plasma level already during the infusion period, insufficient response, and questionable compliance on oral medication were associated. Due to large interindividual differences of plasma levels by a factor of 10, measurements before and after switching are required.

Administration, Oral↗
PubMed1997

Urinary excretion of cortisol, norepinephrine, testosterone, and melatonin in panic disorder.

Nocturnal urinary cortisol, norepinephrine, epinephrine, testosterone, and melatonin secretion patterns were studied in male patients with DSM IV/ICD-10 panic disorder (n = 16) over two series of 5 consecutive nights each. Night-time urinary excretion of cortisol, norepinephrine, and epinephrine was significantly elevated in drug-free patients compared to normal individuals (n = 13). Measurements were repeated after 4 weeks, and the same differences were found again. There were high correlations between the first and the second series of measurements. Testosterone and melatonin levels did not differ between panic patients and controls.

Adult↗
PubMed1997

Endocrine correlates of personality traits: a comparison between emotionally stable and emotionally labile healthy young men.

An initial sample of 120 healthy young men was screened by a personality questionnaire and 15 subjects each with highest and lowest scores respectively on emotionality (emotionally labile, EL subjects and emotionally stable, ES subjects) were recruited for a study on the relationship between the degree of emotionality and the basal secretion of stress-sensitive hormones during night-time. The nocturnal urinary excretion of cortisol, testosterone, adrenaline, noradrenaline and melatonin was measured over a period of 5 consecutive nights. The average amounts of each hormone excreted per night were not different between the two extreme groups. The variability of the excretion during the 5 nights of cortisol and testosterone, but not of adrenaline, noradrenaline and melatonin, was significantly higher in EL compared to ES subjects. The larger fluctuations in the nocturnal secretion of these two (and no other) hormones in EL subjects indicate that emotional lability is associated with a more labile regulation of cortisol and testosterone secretion. The observed intraindividual variability of basal stress hormone secretion may contribute to the vast interindividual variability noticed in psychoneuroendocrine stress research, especially in emotionally labile subjects.

Adolescent↗
PubMed1996

Rat strain differences in the vulnerability of serotonergic nerve endings to neurotoxic damage by p-chloroamphetamine.

Substituted amphetamines are known to selectively destroy serotonin (5-HT) nerve endings in distant projection fields of the dorsal raphe nuclei and the systemic administration of these drugs is widely used in investigations of the role of the central 5-HT system and of the mechanisms involved in their toxicity. Until now Sprague-Dawley rats were almost exclusively used for this purpose and the findings were thought to apply to other strains as well. We compared the long-term effects of the administration of different doses of para-chloroamphetamine (PCA) on three specific markers of the density of 5-HT presynapses, [3H]-paroxetine binding to 5-HT-transporters, tryptophan hydroxylase apoenzyme contents, and 5-HT levels in the frontal cortex of Sprague-Dawley and Wistar rats. PCA-treatment caused a dose dependent decline of all three parameters which was much more pronounced in Sprague-Dawley compared to Wistar rats. An i.p. dose of 4 mg PCA/kg body weight, which caused a severe, about 90% reduction of all three parameters of 5-HT innervation in Sprague-Dawley rats was almost ineffective in Wistar rats. The dose of 8 mg/kg which was required to eliminate about 80% of cortical 5-HT presynapses in Wistar rats was already lethal to Sprague-Dawley rats. The reasons of this different susceptibility of the 5-HT system in the two rat strains are unknown. Their elucidation will contribute to a better understanding of inherited differences in individual vulnerability to the neurotoxic effects of substituted amphetamines. The combined measurements of transporter density, of tryptophan hydroxylase apoenzyme contents, and of 5-HT levels is a powerful tool for the assessment of experimentally induced changes in the density of 5-HT innervation in distant projection fields of the raphe nuclei.

Animals↗
PubMed1996

Diurnal variation of corticotropin-releasing factor binding sites in the rat brain and pituitary.

1. Corticotropin-releasing factor (CRF) is thought to be involved in the regulation of the diurnal activity of the hypothalamus-pituitary-adrenal (HPA) axis and to act as a neurotransmitter in the brain. To date it is unknown whether the binding sites of the central CRF system are subject to diurnal variations. 2. We measured the number of CRF binding sites over the course of a complete 24-hr light-dark cycle in the pituitary, amygdala, bed nucleus of the stria terminalis (BNST), cingulate cortex, visceral cortex, paraventricular nucleus of the hypothalamus, hippocampus, and locus ceruleus of rats by in vitro receptor autoradiography with iodinated ovine CRF. A 24-hr time course was also established for plasma CRF and corticosterone. 3. The diurnal pattern of plasma CRF does not correlate with the pattern of plasma corticosterone. Within the brain, CRF binding in the basolateral nucleus of the amygdala showed a U-shaped curve with maximum levels in the morning and a wide hallow between 1500 and 0100. A biphasic profile with a small depression in the afternoon and a more pronounced depression in the second half of the activity period is characteristic for the other brain areas and the pituitary. The profile for the pituitary correlates with those for the BNST and the area of the locus ceruleus. Furthermore, the diurnal pattern of CRF binding sites in the BNST correlates with that of the hippocampus, and the daytime pattern of the visceral cortex is similar to that of both the hippocampus and the BNST. 4. Since the CRF-binding profiles in the brain and the pituitary clearly differ from the profiles of both plasma CRF and corticosterone, one may assume that the diurnal pattern of central CRF binding sites is not directly coupled to the activity of the HPA axis.

Animals↗
PubMed1996

The central adaptation syndrome: psychosocial stress as a trigger for adaptive modifications of brain structure and brain function.

This review makes an attempt to combine data from biological and psychosocial stress literature and to suggest an alternative interpretation of the relationship between stress and disease. It rearranges the presently available knowledge on the short- and long-term effects of stress on many different aspects of brain structure and brain function in the form of a new conceptualization of the biological role of the stress response. The higher associative brain structures are not only the sites in which environmental and psychosocial demands are recognized and from which a less or more systemic, i.e. controllable or uncontrollable, stress response is initiated. They are also the sites which are primarily affected in the course of the stress response: the stress response acts as a trigger for the adaptive modification of the structure and the function of the brain of higher vertebrates and serves thus to adjust, in a self-optimizing manner, the behavior of an individual to the ever-changing requirements of its external world. This novel concept summarizes a large amount of information into a framework that lends itself to testable strategies for future research.

Adaptation, Physiological↗
PubMed1996

Nocturnal plasma melatonin levels after flunitrazepam administration in healthy subjects.

Polysomnographic sleep patterns and melatonin secretion were investigated in 5 young (age 25.6 +/- 1.1 years) and 5 middle-aged (age 49.4 +/- 5.4 years) healthy male subjects after intravenous administration of 1 mg flunitrazepam and placebo in a randomized, double-blind and cross-over setting. The area under the curve (AUC) of total nocturnal melatonin plasma concentration decreased 23.3 +/- 11.5% in young subjects (P < or = 0.05) and 39.3 +/- 5.2% in middle-aged subjects (P < or = 0.05) after flunitrazepam infusion compared with placebo infusion. Differences in nocturnal peak values of melatonin were 5.4 +/- 22.0% in young subjects (not significant) and 34.0 +/- 14.7% in middle-aged subjects (p < or = 0.05). Flunitrazepam significantly (P < or = 0.05) improved sleep latency and the number of sleep stage changes in the group of all subjects. These results show that, although the benzodiazepine flunitrazepam improves sleep, it reduces the nocturnal secretion of melatonin, and therefore alters the circadian rhythm of a hormone which is supposed to play a special role in circadian sleep-wake rhythmicity.

Adult↗