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H Rommelspacher

Publications and source records attributed to H Rommelspacher.

At least 19 recordsLinked to original sources
PubMed1991

[3H]harman binding experiments. I: A reversible and selective radioligand for monoamine oxidase subtype A in the CNS of the rat.

Harman (1-methyl-beta-carboline) is an endogenous compound with neurotropic properties in rats and humans. In a novel in vitro binding assay, the binding site of [3H]harman has been characterized in the rat crude mitochondrial (P2) fraction. The binding was saturable and reversible. Only a single high-affinity binding site was detected by kinetic, saturation, and displacement analyses in the cerebral cortex of the rat. The linear Scatchard plots revealed equilibrium dissociation constant (KD) values of approximately 2.5 nM at 0 degrees C, approximately 9 nM at 23 degrees C, and approximately 30 nM at 37 degrees C. Among six CNS regions (hypothalamus, hippocampus, cerebral cortex, striatum, cerebellum, and spinal cord), the highest density of binding sites (Bmax) was determined in the hypothalamus (approximately 5.5 pmol/mg of protein) and the lowest in the spinal cord (approximately 2.0 pmol/mg of protein). Several drugs known to affect serotonergic, adrenergic, dopaminergic, cholinergic, or GABAergic neurotransmission inhibited specific binding at best in the micromolar range. In contrast, potent and selective inhibitors of monoamine oxidase subtype A were active in the lower and middle nanomolar range. The displacing potency (apparent Ki) of substrates and inhibitors of monoamine oxidase correlated positively and highly significantly with the corresponding values of the inhibition of monoamine oxidase activity of subtype A (r = 0.92, p less than 0.001, n = 17) but not of subtype B (r = -0.47, p greater than 0.05, n = 15). In conclusion, [3H]harman was identified as a specific ligand of the active site of the A subtype of monoamine oxidase in rat brain.

Animals↗
PubMed1991

[3H]harman binding experiments. II: Regional and subcellular distribution of specific [3H]harman binding and monoamine oxidase subtypes A and B activity in marmoset and rat.

[3H]Harman (1-[3H]methyl-beta-carboline) was used in a novel radioligand binding assay to label selectively and with high affinity monoamine oxidase (MAO) type A. The concentration of the enzyme was determined in six CNS regions of the primate species marmoset (Callithrix jacchus) and of the rat: hypothalamus, hippocampus, cerebellum, cerebral cortex, striatum, and spinal cord. The specific [3H]harman binding in the CNS of the marmoset reveals the same pharmacological profile and other characteristics (affinity, saturability, and reversibility) as in the CNS of the rat. The regional distribution of the [3H]harman binding density (Bmax) in the CNS exhibits a distinct pattern in the marmoset and the rat and a 35 (hypothalamus) to 75% (hippocampus) lower Bmax in the marmoset than in the rat. The Bmax values of [3H]harman binding in the CNS of the marmoset and the rat combined as well as those from visceral organs of the rat (liver, heart, lung, thymus, spleen, and kidney) correlated positively and highly significantly with the respective Vmax values of specific MAO activity of the A type but not of the B type, determined with kynuramine as the substrate. In subcellular fractionation experiments with rat cerebral cortex, the highest [3H]harman binding density (Bmax) and MAO-A activity (Vmax) were detected in mitochondrial fractions and severalfold lower values in the synaptosomal membrane fraction. In conclusion, we suggest that [3H]harman binding is a biochemical tool as a selective marker to quantify MAO-A in the CNS of different mammalian species as well as in extraneuronal tissues.

Aging↗
PubMed1991

Plasma norharman (beta-carboline) levels are elevated in chronic alcoholics.

Based on the hypothesis that condensation products of neurotransmitters with aldehydes are involved in the pathogenesis of alcoholism, aromatic beta-carbolines (norharman and harman) were measured in the blood plasma of alcoholics and nonalcoholics. The identity of the extracted compounds was confirmed by various elution conditions of the high performance liquid chromatography (HPLC), newly developed radioreceptor assays, and the mass spectrum of norharman. The levels of norharman and harman in nonalcoholics were unchanged after a load with ethanol (1 g/kg body weight). The norharman levels of the alcoholics were significantly higher than that of the nonalcoholic controls (99.5 +/- 26.6 pg/ml vs. 26.9 +/- 10.7 pg/ml; p less than 0.001) and did not change significantly during a 3-week detoxication period. In the subgroup of alcoholics with delirium or hallucinosis, a slight increase of norharman during detoxication could be detected while in alcoholics with vegetative withdrawal symptoms norharman levels dropped slightly over time (p = 0.07). No difference was found with respect to harman between nonalcoholics and alcoholics. These results suggest disturbed regulatory processes in the formation and/or metabolism of norharman in alcoholics. Further investigations are needed to reveal a possible marker function of norharman in alcoholic patients.

Adolescent↗
PubMed1991

[Pathobiochemistry and pharmacotherapy of alcohol withdrawal delirium].

The spectrum and time course of different symptoms during alcohol withdrawal may be caused by the involvement of various neurotransmitter systems that are differentially vulnerable to the effects of ethanol. Withdrawal symptomatology results from increased activity of excitatory mechanisms (NMDA-receptor, catecholamines among others) and from reduced functioning of inhibitory receptors (GABAA-, alpha 2-adreno-receptor among others). The neuronal mechanisms are subject to different dynamics of restitution following intoxication. Some of these probably contribute to long-lasting changes in CNS functions by "kindling" processes. Therapeutic guidelines are deduced from results of basic research and clinical trials. It is concluded that clomethiazole and benzodiazepines are superior in treating delirium tremens and certain risk-patients, whereas carbamazepine and clonidine may be helpful in moderate withdrawal syndromes or as adjunctive agents. However, the need for improved methodological standards of method in clinical research is evident.

Alcohol Withdrawal Delirium↗
PubMed1991

Beta-carbolines and tetrahydroisoquinolines: detection and function in mammals.

beta-Carbolines occur in man and rat. The concentration in various tissues is about 100 to 1000 times lower than that of classical neurotransmitters. Administration of beta-carbolines in animals induces overlapping but not identical activity profiles. The molecular modes of action differ. For example, harman (1-methyl-beta-carboline) acts as an endogenous inhibitor of monoamine oxidase [E.C. 1.4.3.4.], subtype A, whereas norharman (beta-carboline) probably acts by stimulation of a specific beta-carboline receptor which is different from the benzodiazepine-GABA receptor complex. There is substantial evidence that tetrahydroisoquinolines occur under physiological conditions as well. Whether tetrahydropapaveroline serves as a precursor of morphinanes in mammals, as has been found in opium poppies, remains to be elucidated.

Animals↗
PubMed1990

[3H]Harman labels selectively and with high affinity the active site of monoamine oxidase (EC 1.4.3.4) subtype A (MAO-A) in rat, marmoset, and pig.

[3H]Harman was used in binding studies with CNS tissue of rat, pig, and marmoset and with visceral organs of the rat. In the mitochondrial fractions of the CNS of the 3 species [3H]harman binding exhibits the same pharmacological profile in displacement studies. A detailed analysis reveals a high specificity for MAO-A. Furthermore, we applied [3H]harman binding to quantify the MAO-A content in 6 CNS regions of each species as well as in 6 visceral organs of the rat.

Animals↗
PubMed1990

Ethanol reduces tolerance, sensitization, and up-regulation of D2-receptors after subchronic haloperidol.

To study the interrelationships between dopamine D2-receptor density and behavioral responses after chronic treatment with neuroleptics female Wistar rats received haloperidol (HP; 14 mg/l), ethanol (ETOH; 5 vol.%), a combination of both, or tap water as drinking fluids for one or two weeks. Mean intake doses ranged between 1.28 and 1.48 mg/kg/day (HP) and between 3.7 and 4.8 g/kg/day (ETOH). HP administered for one or two weeks raised the number of [3H]spiroperidol binding sites in the striatum by 55%. Concomitant administration of ETOH diminished the increase of Bmax to 23%. The up-regulation was even reversed when ETOH was added with a delay of one week, although the drug alone had no effect on dopamine-D2-receptor density. KD values were not substantially affected. During HP treatment the rats established a tolerance to the motor sedation which was measured by circadian motility recordings. Coadministration of ETOH reduced the development of tolerance, the activity remained at a depressed level. Acute applications of HP (0.3, 0.6, and 0.9 mg/kg, or saline, respectively) also revealed tolerance to the drug for various behavioral responses (exploratory locomotion, rearing, rotarod performance, catalepsy). The tolerance was reduced in all those animals which had received combinations of ETOH and HP. The reduction was most pronounced for the cataleptic response. Pretreatment with ETOH alone had no effect. Sensitization to dopamine agonists was studied by apomorphine-induced stereotypies (licking, sniffing, and forepaw scratching). As expected, chronic HP enhanced the responses. The increased number of stereotypies was reduced in rats pretreated with the combination, although ETOH alone did not affect the response. The reduction was most pronounced for licks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effects of desipramine on rat behavior are prevented by concomitant treatment with ethanol.

Ethanol prevents the decrease of the number of beta-adrenoceptors in the cerebral cortex induced by chronic treatment of rats with desipramine. The activation of the adenylate cyclase, the second messenger, by beta-adrenergic agonists is reduced somewhat less than after treatment with desipramine alone. The present paper examined the hypothesis that ethanol inhibits the neuronal adaptation to desipramine chronic treatment at the functional level as well. Desipramine reduced exploratory behavior (crossings, rearings) as did ethanol. Combined treatment attenuated the effect of desipramine. Cognitive performance was investigated using an active avoidance paradigm. Desipramine-treated rats did not learn the task in contrast to control animals. Again, combination treatment with ethanol improved the ability of the rats to perform the task. The activity of cerebral beta-adrenergic mechanisms was assessed by injection of salbutamol, a beta-adrenoceptor agonist in rats pretreated with 5-hydroxytryptophan (5-HTP). The augmentation of the 5-HTP-induced wet dog shake behavior by salbutamol was observed in all animals independent of the chronic treatment. However, rats treated with desipramine were less active than those treated with tap water or ethanol. The effect of desipramine in the presence of a high concentration of salbutamol was attenuated by ethanol. The observed increase of the number of wet dog shakes correlates with the function of these receptors. In two paradigms, spontaneous motility and apomorphine-induced hypothermia, ethanol did not affect the action of desipramine. It is noteworthy that desipramine acted in both situations within a short time period (minutes to hours). The findings strongly suggest that ethanol can prevent adaptive changes in the brain induced by chronic treatment with the antidepressant desipramine. This is of special interest since the adaptation of beta-adrenoceptors is thought to be critical for the antidepressant efficacy of various therapeutic interventions applied in psychiatric practice.

5-Hydroxytryptophan↗
PubMed1989

Formation of thiazolidine-4-carboxylic acid represents a main metabolic pathway of 5-hydroxytryptamine in rat brain.

Incubation of 5-hydroxytryptamine (5-HT) with rat brain homogenate resulted in the formation of (4R)-2-[3'-(5'-hydroxyindolyl)-methyl]-1,3-thiazolidine-4-carboxyl ic acid (5'-HITCA) as the major metabolite. The substance represents the condensation product of 5-hydroxyindole-3-acetaldehyde with L-cysteine. The chemical structure was confirmed by chromatographic and chemical methods as well as by fast atom bombardment mass spectrometry. Incubation of 5-HT in the presence of L-cysteine yielded the thiazolidine as the main metabolite up to 4 h. Under these conditions, the concentration of 5-hydroxyindole-3-acetic acid (5-HIAA) amounted to about 20% and 57% of 5'-HITCA (0.5 h and 4 h, respectively). In contrast to these findings, indole-3-acetic acid (IAA) was identified as the major metabolite when tryptamine was incubated under similar conditions. (4R)-2-(3'-Indolylmethyl)-1,3-thiazolidine-4-carboxylic acid (ITCA) was found to be the main conversion product of tryptamine only during the first 30 min. To investigate the fate of the thiazolidines, radiolabelled and unlabelled ITCA was incubated with rat brain homogenate. The compound was degraded enzymatically and rapidly. Subcellular fractionation revealed that the enzyme activity was present mainly in the cytosolic fraction whereas the preparation of mitochondria showed less activity. The responsible enzyme is presumably a carbon-sulfur lyase (EC 4.4.1.-). The major metabolite was isolated by HPLC and identified by mass spectrometry as well as by comparison with reference compounds to be IAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Biochemical characterization of [3H]tryptamine binding sites from rat brain.

Rat brain membranes were treated with different protein modifying reagents, all of which were able to reduce [3H]tryptamine binding. However, inactivation by N-ethylmaleimide and iodoacetamide only was counteracted by coincubation with tryptamine. Thus, the [3H]tryptamine binding molecule is a membrane protein with an essential sulfhydryl group at the binding site. After incubation of digitonin-solubilized membranes with seven different lectins, no precipitation of [3H]tryptamine binding sites was observed. On concanavalin A and wheat germ agglutinin affinity chromatography, no [3H]tryptamine binding activity was found to be specifically bound. Therefore, the [3H]tryptamine binding protein appears to be devoid of lectin binding carbohydrate residues.

Animals↗
PubMed1988

Demonstration of a distinct class of high-affinity binding sites for [3H]norharman [( 3H]beta-carboline) in the rat brain.

Specific binding sites were demonstrated for some beta-carbolines in the rat brain with [3H]norharman as a ligand. The ligand displayed a high affinity for synaptosomal membranes which had been fractionated by a sucrose gradient. The calculated apparent KD value was 1.55 nmol/l and the maximum number of binding sites 148 fmol/mg protein. Displacement studies showed an exclusive specificity for a small group of beta-carbolines but not for the previously described inverse agonists at the benzodiazepine receptor nor for tryptamine and other indoles, as well as pargyline, a monoamine oxidase inhibitor. Further analysis revealed other binding sites for [3H]norharman, with an apparent KD value of 36 nmol/l that are presumably located on mitochondrial membranes. Binding to these sites was also not displaced by pargyline. Pargyline displaced [3H]norharman from a third population of binding sites on mitochondrial membranes with the apparent KD value of 46 nmol/l. These findings could explain the pharmacological effects of norharman and other beta-carbolines in vivo.

Alkaloids↗
PubMed1988

Formation of 1-methyl-beta-carbolines in rats from their possible carboxylic acid precursor.

In vivo metabolism of 1-methyl-1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (1-CTHH), a possible precursor of the endogenous beta-carbolines tetrahydro-harman (THH) and harman was investigated in rats. Following intraperitoneal injection of [4-14C]1-CTHH, a rapid distribution of the radioactivity in the tissues was observed. The highest radioactivity was measured in the kidney and the lowest in the brain as well as in the fat tissue. Approximately 55% of the administered dose was excreted in the urine within 90 min. The radioactivity in the urine consisted of unchanged 1-CTHH (greater than 90%) besides harmalan and trace amounts of harman. Harmalan represents the major degradation product of 1-CTHH; it could be identified in all tissues examined and in the urine. The concentration in the blood, however, was low at all time points investigated. The peak concentration of harmalan in most tissues was measured between 15-30 min after injection. A time-dependent formation of THH was found in the lung and spleen indicating an important role of these organs in the biosynthesis of THH. Furthermore, the metabolism of [4-14C]1-CTHH in the brain was studied following intracerebroventricular injection. The formation of harmalan in the brain was not affected by pretreatment with the aromatic amino acid decarboxylase inhibitor NSD 1015. Determination of the harmalan concentration in several brain regions revealed a high level in the hippocampus and hypothalamus and a small concentration in pons, corpus striatum, cerebellum and cerebral cortex 20 min after injection. The analyses of the

Animals↗
PubMed1988

Sleep deprivation and imipramine binding sites in depressed patients and healthy subjects.

The influence of sleep deprivation on 3H imipramine binding was investigated in blood platelets of 32 depressed patients and 15 healthy subjects. The effect of sleep deprivation was not statistically different in either group. Changes of Bmax associated with sleep deprivation were compensated for by reciprocal changes of Kd in the group of patients, suggesting altered regulatory mechanisms. A comparison of binding characteristics of responders and nonresponders to sleep deprivation revealed no difference between groups. If the patients were divided by a biological criterion (number of binding sites), a prediction of clinical response to sleep deprivation was possible.

Adult↗