Gerald Huether

Effect of tryptophan administration on circulating melatonin levels in chicks and rats : evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract

The administration of L-tryptophan (Trp, 150-300 mg/kg) to rats and chicks causes a rapid and dose-dependent elevation of circulating melatonin. The elevation of serum melatonin was greater after oral compared to the intraperitoneal route of administration of the same dose of Trp (150 mg/kg). The Trp-induced increase of circulating melatonin was unaffected by prior pinealectomy but was almost abolished by a partial ligature of the portal vein. The Trp-induced increase of melatonin in the portal blood preceded that in the systemic circulation. The gut contains considerable amounts of melatonin and the Trp-induced elevation of melatonin was greater in the duodenum compared to the pineal or the blood. The enterochromaffin cells of the gastrointestinal tract appear to be the major source of the Trp-induced increment of circulating melatonin. The possibility is discussed that the sedating, sleep inducing effects of Trp are mediated by the Trp-induced elevation of circulating melatonin.

Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia.

Recent research provides evidence for an interaction between sleep and the activation of the hypothalamic-pituitary-adrenal (HPA)-axis, but detailed studies in patients are still missing. We investigated hourly evening and nocturnal plasma cortisol secretion and sleep in seven male patients with severe chronic primary insomnia and age- and gender-matched controls. Evening and nocturnal cortisol levels were significantly increased in patients. Evening cortisol correlated with the number of nocturnal awakenings in patients and controls. Additionally, patients showed significant correlations between sleep parameters and the first 4 h of nocturnal cortisol secretion. These results are indicative of changes in the HPA system in insomnia and may reflect a pathophysiological mechanism of chronic insomnia resulting in a vicious cycle of both disturbed HPA functions and chronic insomnia according to the arousal hypothesis of insomnia.

Age-associated changes in the densities of presynaptic monoamine transporters in different regions of the rat brain from early juvenile life to late adulthood.

The binding parameters of highly selective ligands of serotonin (5-HT) transporters ([3H]paroxetine), noradrenaline (NE) transporters ([3H]nisoxetine), and of dopamine (DA) transporters ([3H]GBR-12935) were determined on membrane preparations from frontal cortex, striatum, midbrain and brain stem of Wistar rats on postnatal days 25, 50, 90 and 240, i.e., from the time of weaning till late adulthood. No age-dependent alterations in the affinity-parameters (K(D)-values) of all three monoamine transporters were observed. Age-associated changes in B(max)-values of the binding of all three specific ligands were most pronounced in the phylogenetically younger, late maturing brain regions (frontal cortex, striatum). Most likely, these changes reflect age-related changes in 5-HT, NE and DA-innervation densities. In the frontal cortex, 5-HT-transporter density increased steadily from weaning (day 25) till late adulthood, whereas the density of NE-transporters was highest at weaning, declined till puberty (day 50) and remained at this level until old age. DA-transporter density in the frontal cortex was not reliably measurable by [3H]GBR-binding assays. In the striatum, DA-transporter density increased till puberty and declined thereafter considerably and steadily to about one-fourth of the pubertal values at old age. No such age-associated changes in DA-transporter density were seen in the midbrain. Densities of 5-HT and NE remained at the level reached already at weaning until old age in the striatum, midbrain and brain stem. These findings provide the first comprehensive description of the normally occurring changes in the densities of all three presynaptically located monoamine transporters in the rat brain throughout the life span from weaning to late adulthood.

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.

Early Methylphenidate Administration to Young Rats Causes a Persistent Reduction in the Density of Striatal Dopamine Transporters

Methylphenidate is widely and effectively used for the treatment of attention deficit hyperactivity disorder during early childhood and adolescence, but until now possible effects of this treatment on brain development and the maturation of monoaminergic systems have not been investigated systematically. This experimental animal study describes the effects of methylphenidate administration (2 mg/kg/day) for 2 weeks to very young (prepubertal) and somewhat older (postpubertal) rats on the densities of dopamine, serotonin, and norepinephrine transporters in the striatum and in the midbrain. As shown by ligand-binding-assays, the K(D) values of all three transporters were unaffected by this treatment. No alterations were found for the Bmax values of [3H]-paroxetine and [3H]-nisoxetine binding, but the density of dopamine transporters (Bmax values of [3H]-GBR binding) in the striatum (but not in the midbrain) was significantly reduced after early methylphenidate administration (by 25% at day 45), and this decline reached almost 50% at adulthood (day 70), that is, long after termination of the treatment. This is the first empirical demonstration of long-lasting changes in the development of the central dopaminergic system caused by the administration of methylphenidate during early juvenile life.

Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia

Abstract: Polysomnographic sleep patterns and melatonin secretion were investigated in 10 patients (age: 41.3 ± 9.5 years) who suffered from chronic primary insomnia and complained predominantly about difficulties in maintaining sleep and in five healthy controls (age 27.2 ± 0.7 years). Nocturnal plasma melatonin concentrations were obtained hourly, measured by direct radioimmunoassay and statistically compared between insomniacs and controls with age as a covariate. Plasma melatonin levels in the patient group tended to begin increasing earlier in the evening and were significantly (P ± 0.01) lower during the middle of the night (peak value 82.5 ± 26.5 pg/ml) than in the healthy controls (peak value 116.8 ± 13.5 pg/ml). Among the patients, the most severely reduced nocturnal plasma melatonin levels were found in those patients with a history of sleep disturbance lasting for longer than five years (N = 6; age 41.8 ± 11.7 years; duration 15.3 ± 5.9 years; peak value 72.1 ± 25.0 pg/ml); whereas those chronic insomniacs affected for fewer than five years had relatively higher nocturnal levels (N = 4; age 40.6 ± 6.5 years; duration 3.8 ± 1.5 years; peak value 98.2 ± 23.9 pg/ml). These results show that the circadian rhythm of melatonin secretion is disturbed in patients with chronic primary insomnia, and that the nocturnal plasma melatonin secretion is increasingly more affected the longer the patients are unable to maintain a regular sleep pattern.

Presence of melatonin in the human hepatobiliary-gastrointestinal tract

A variety of speculations about the possible origin and physiological role of the neurohormone melatonin in the gastrointestinal tract exist. However, the experimental evidence supporting any of these theories is not substantial and are missing for humans. We studied the distribution of melatonin which was measured with radioimmunoassay in the following compartments and organs of the human hepatobiliary-gastrointestinal tract: bile (obtained by endoscopic retrograde cholangiopancreaticography), peripheral venous and portal venous blood (obtained from patients undergoing liver transplantation), endoscopically derived biopsies (mainly consisting of mucosa and submucosa) of stomach, duodenum, large intestine as well as in resected liver tissue. Melatonin concentrations in gastrointestinal mucosa were between 136 +/- 27 pg/100 mg (stomach) and 243 +/- 37 pg/100 mg (descending colon, each n = 5). Biliary melatonin concentrations (85 +/- 45 pg/ml) correlated well with plasma concentrations (55 +/- 38 pg/ml, each n = 14) and a considerable amount of melatonin (about 51 ng/24 hours) appears to be excreted into the gut via the bile duct. Melatonin concentrations were slightly higher in portal than in peripheral venous blood and also the liver contained higher concentrations of melatonin than the blood. In conclusion the presence and distribution of melatonin in human gut, bile, liver and portal blood and the various reports on modulatory actions of melatonin on gut and liver functions suggest that melatonin may act as a mediator of inter-organ communication between gut and liver.

The metabolic fate of infused L-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites*

Abstractl-Tryptophan (Trp) was widely used as a natural tool for the support of serotonin-mediated brain functions and as a challenge probe for the assessment of serotonin-mediated neuroendocrine responses. The metabolic fate of the administered Trp and the kinetics of the accumulation of Trp metabolites in the circulation, however, have never thoroughly been investigated.This study describes the time- and dose-dependent alterations in the plasma levels of various Trp metabolites and large neutral amino acids after the infusion of Trp to healthy young men (1, 3 and 5 g; placebo-controlled, double-blind, cross-over study during day- and night-time).The major Trp metabolites (kynurenine, indole acetic acid and indole lactic acid) in plasma increased dose-dependently but rather slowly after Trp administration to reach their maximal plasma levels (up to 10-fold after the 5 g dose) at about 3 h p.i., and remained at an elevated level (about 5-fold) for up to 8 h. N-acetyl-Trp and 5-hydroxy-Trp rose rapidly and massively after Trp infusions, at the 5 g dose more than 200- and 20-fold, respectively, and declined rapidly to about 5-fold baseline levels within 2 h. Whole blood serotonin levels were almost unaffected by the Trp infusions. A rather slow increase of 5-hydroxyindole acetic acid was seen, reaching maximum values (3-fold at the 5 g dose) at about 2 h after the infusion of Trp. Additionally, a dose-dependent rise of circulating melatonin was observed afterl-Trp infusions. The administration ofl-Trp caused a depletion of the concentrations of the other large neutral amino acids and a dose dependent decrease of the ratio between plasma tyrosine and the sum of the plasma concentrations of the other large neutral amino acids. Apparently, none of the existing pathways of peripheral Trp metabolism is saturated by its substrate, Trp in men. At least some of the central effects reported afterl-Trp administration may be mediated by the Trp-stimulated formation of neuroactive metabolites or by the decreased availability of tyrosine for catecholamine synthesis.

STRESS AND THE ADAPTIVE SELF-ORGANIZATION OF NEURONAL CONNECTIVITY DURING EARLY CHILDHOOD

A conceptual framework is proposed for a better understanding of the biological role of the stress‐response and the relationship between stress and brain development. According to this concept environmental stimuli (in children mainly psychosocial challenges and demands) exert profound effects on neuronal connectivity through repeated or long‐lasting changes in the release of especially such transmitters and hormones which contribute, as trophic, organizing signals, to the stabilization or destabilization of neuronal networks in the developing brain. The increased release of noradrenaline associated with the repeated short‐lasting activation of the central stress‐responsive systems in the course of the stress‐reaction‐process to psychosocial challenges which are felt to be controllable acts as a trigger for the stabilization and facilitation of those synaptic and neuronal pathways which are activated in the course of the cognitive, behavioral and emotional response to such stressors. The long‐lasting activation of the central stress‐responsive systems elicited by uncontrollable psychosocial conflicts in conjunction with the activation of glucocorticoid receptors by the sustained elevation of circulating glucocorticoid levels favors the destabilization of already established synaptic connections and neuronal pathways in associative cortical and limbic brain structures. The facilitation and stabilization of neuronal pathways triggered by the experience of controllable stress is thus opposed, attenuated or even reversed in the course of long‐lasting uncontrollable stress. This destabilization of previously established synaptic connections and neuronal pathways in cortical and limbic brain structures is a prerequisite for the acquisition of novel patterns of appraisal and coping and for the reorganization of the neuronal connectivity in the developing brain. Alternating experiences of repeated controllable stress and of long‐lasting uncontrollable stress are therefore needed for the self‐adjustment of neuronal connectivity and information processing the developing brain to changing environmental (psychosocial) demands during childhood. The brain structures and neuronal circuits involved in the regulation of behavioral responding become thus repeatedly reoptimized and refitted, not the changing conditions of life per se but rather to those conditions which are still able to activate the central stress responsive systems of an individual at a certain developmental stage.

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.