Cytoplasmic and axoplasmic density variations in relation to hyperactivity

Summary The density of the cytoplasm and axoplasm of the anterior horn cell in rats was determined by X-ray microradiography. The average density of the cytoplasm of more than 400 cells from control rats was 0.31 g/³, while that of over 600 cells from rats fed IDPN (- iminodipropionitrile) was 0.43 g/³.Hyperactivity developed during the first 5 weeks and was associated with a gradual increase in cytoplasmic density to 0.51 g/³.At 6 weeks there was a drop in density to 0.36 g/³ which coincided with the appearance of axonal balloons having a density of 0.17 g/³.During the 7–12th week on the diet, the cytoplasmic density showed a gradual increase to 0.59 g/³ and the balloons to 0.29 g/³.The volume of the nerve cells remained fairly constant. The density increases were discussed in relation to hypertrophy, dystrophy, and hyperactivity.

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Zusammenfassung Die Dichte des Cytoplasmas und Axoplasmas der Vorderhornzellen von Ratten wurde durch Röntgenmikroradiographie bestimmt. Die mittlere Dichte des Cytoplasmas von mehr als 400 Zellen der Kontrollratten war 0,31 g/³, während die mittlere Dichte von mehr als 600 Zellen der Ratten, die mit IDPN (- iminodipropionitrile) gefüttert waren, 0,43 g/³ war.Hyperaktivität entwickelte sich während der ersten 5 Wochen und war mit einer progressiven Zunahme der Cytoplasmadichte bis auf 0,51 g/³ verbunden.Nach 6 Wochen sank die Dichte auf 0,36 g/³. Diese Tatsache traf mit dem Auftreten der Axonauftreibungen zusammen, die eine Dichte von 0,17 g/³ hatten.Nach 7–12 Wochen zeigte die Cytoplasmadichte eine progressive Zunahme auf 0,59 g/³ und die der Auftreibungen eine Zunahme auf 0,29 g/³.Das Volumen der Nervenzellen blieb ziemlich konstant.Die möglichen Zusammenhänge zwischen Zunahme der Dichte, Hypertrophie, Dystrophie und Hyperaktivität werden dargestellt.

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Supported by U. S. Public Health Grant NB 1305.     

Equol and other compounds from bovine urine as monoamine oxidase inhibitors

Summary Equol, its methylated derivative, and a carbazole, all isolated from bovine urine, are relatively potent inhibitors of monoamine oxidase with IC₅₀ values of 158, 28, and 16M respectively (using 83M tyramine as substrate). The probable dietary origin of these compounds suggests that natural monoamine oxidase inhibitors may be more widespread than had previously been suspected.     

Concentrations of remoxipride and its phenolic metabolites in rat brain and plasma. Relationship to extrapyramidal side effects and atypical antipsychotic profile

Summary The cataleptic effect of remoxipride was examined in the horizontal bar test after i.v.,i.p. and s.c. administration to male rats. Remoxipride induced immediate catalepsy after high i.v. doses (ED₅₀=49 mol/kg) while peak effects were seen 60–90 min after i.p. administration (ED₅₀=38 mol/kg). Following s.c. administration remoxipride failed to produce a statistically significant catalepsy in the 20–100 mol/kg dose range (ED₅₀ > 100 mol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED₅₀=0.4 mol/kg) than after i.p. or s.c. administration (ED₅₀=0.9 mol/ kg). The atypical antipsychotic profile of remoxipride was more pronounced when the compound was given i.v. or s.c. as compared with the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of remoxipride and its active phenolic metabolites FLA 797(–) and FLA 908(–) were measured by high performance liquid chromatography. The 40 mol/kg dose of remoxipride resulted in plasma and brain concentrations of remoxipride which were 300–1000-fold higher (depending on the route of administration) than the most potent of the phenolic metabolites, e.g., FLA 797(–). The plasma and brain concentrations of remoxipride and its phenolic metabolites were related to DA D₂ receptor blocking potency and to the temporal course and effectiveness to induce catalepsy. This analysis suggested that the unbound concentrations of the phenolic metabolites were too low to play a major role in the DA blocking action of remoxipride. However, FLA 797(–) may contribute marginally to the cataleptic effects following high (i.p.) doses of remoxipride.     

Dose response relationship between plasma ACTH and cortisol after the infusion of ACTH1–24

Summary The authors examined the dose response relationship between plasma ACTH and cortisol concentrations after the administration of various doses of ACTH_1–24 (0.025 g, 0.125 g, 0.25 g, 1 g, 250 g) in dexamethasone-suppressed normal volunteers. A logarithmic dose-response relationship between the dose of ACTH administered and plasma cortisol concentration was found. Although there was considerable variability in plasma ACTH concentrations, there was, however, a definite correlation between area under the curve for ACTH and area under the curve for cortisol after the various doses of ACTH.     

Presynaptic effects of gamma-aminobutyric acid on norepinephrine release and uptake in rat pineal gland

Summary The effect of -aminobutyric acid (GABA) on pineal norepinephrine (NE) release was examined in vitro in the rat pineal gland. Exposure of pineal expiants previously loaded with³H-NE to 1–100 M GABA caused a dosedependent decrease of³H-NE release triggered by 60 mM K⁺, with a threshold GABA concentration of 1 M and IC₅₀ of about 10 M. The inhibitory effect of GABA was mimicked by the type B GABA agonist baclofen, displaying a similar dose-response relationship as GABA. The type A GABA agonist muscimol increased depolarization-induced³H-NE release, while the co-incubation with GABA and the type A receptor antagonist bicuculline augmented significantly GABA's depressive effect on³H-NE release. Bicuculline alone brought about a significant decrease of³H-NE release. Neither GABA, nor baclofen, muscimol or bicuculline, modified the spontaneous pineal³H-NE efflux. Assessment of³H-NE uptake at a low NE concentration (0.5 M) indicated that GABA decreased it in a dose-dependent manner (IC₅₀=100 M) through an effect blocked by bicuculline and mimicked by muscimol but not by baclofen; at a 5 M-³H-NE concentration a bicuculline-sensitive GABA augmentation of uptake was found. A kinetic analysis study of the pineal NE uptake process indicated that GABA augmented both Vmax and Km of transmitter uptake. These results indicate that GABA may be a significant regulatory signal for rat pineal sympathetic synapses.     

Single drug therapy for intractable epilepsy

Summary Single drug therapy with either phenytoin or primidone resulted in complete seizure control in 11 of 35 patients (31%) referred to an epilepsy clinic for treatment of uncontrolled chronic epilepsy with complex-partial seizures. Complete seizure control was associated with an increase in the mean plasma concentrations from 14 g/ml to 23 g/ml phenytoin and from 34 g/ml to 40 g/ml phenobarbitone with no change in the antiepileptic drug. Insufficiently low plasma concentrations of less than 11 g/ml phenytoin or phenobarbitone were measured at the first visit in 14 patients (40%). Non-compliance was admitted by eight patients (23%). Optimum single drug therapy is of considerable clinical value in intractable epilepsy with complex-partial seizures.

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Zusammenfassung Eine Monotherapie mit Phenytoin oder Primidon führte zur Anfallsfreiheit bei 11 von 35 Patienten (31%), die wegen schwerbehandelbarer psychomotorischer Anfälle eine Epilepsieambulanz aufsuchten. Anfallsfreiheit trat auf bei einem Anstieg der mittleren Plasmakonzentration von 14 g/ml auf 23 g/ml Phenytoin und von 34 g/ml auf 40 g/ml Phenobarbital. Ein Wechsel der Medikamente war nicht notwendig. Während der ersten Untersuchung wurden bei 14 Patienten (40%) zu niedrige Plasmakonzentrationen von weniger als 11 g/ml Phenytoin oder Phenobarbital gefunden. 8 Patienten (23%) gaben eine unregelmäßige Einnahme der Medikamente (non-compliance) zu. Eine konsequente Monotherapie ist von klinischem Wert für die Behandlung von schwerbehandelbaren Epilepsien mit psychomotorischen Anfällen.

     

Functional changes in cocultures of mesencephalon and striatal neurons from embryonic C57/BL6 mice due to low concentrations of 1-Methyl-4-Phenylpyridinium (MPP+)

Summary 1-Methyl-4-phenylpyridinium (MPP⁺), the active metabolite of 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is taken up into dopaminergic terminals and selectively destroys dopaminergic neurons, serving as a valuable tool in animal model of Parkinson's disease. Cocultures from ventral mesencephalon and neostriatum of embryonic C57/BL6 mouse brains were used to study the sensitivity of dopaminergic neurons to the toxic agent MPP⁺. Cultures were grown for 9 days in vitro and exposed to different concentrations of MPP⁺ for various times. Treatment with (0.1–1.0 M) MPP⁺ for 24 hours decreased³H-dopamine (³H-DA) uptake with an IC₅₀ at 0.2 M. Exposure of cells to 1 M MPP⁺ over time decreased the⁺H-DA uptake to 38% of controls within the first two hours of incubation and to 8% after 48 hours. Loss of tyrosine hydroxylase (TH) positive cells became evident at 0.1 M MPP⁺ (80% of control) leading to maximal toxicity at 10 M (20% of control). MPP⁺ reduced the dopamine content in the cultures in a dose dependent manner (IC₅₀ at 0.1 M) and failed to show reversibility in recovery studies. These findings provide evidence that exposure of MPP⁺ even at low concentrations and for short time in our coculture model results in irreversible toxicity for dopaminergic neurons.     

Morning administration of melatonin antagonizes the antigonadotrophic effect of afternoon injections of melatonin, 5-methoxytryptophol and arginine vasotocin in intact mice

Summary In intact prepubertal mice kept under a long photoperiod subcutaneous afternoon (4.30 p.m.) injections (20 g) but not morning (9.30 a.m.) injections (100 g) of melatonin and 5-methoxytryptophol elicited antigonadotrophic effects. A morning dose (100 g) of methoxytryptophol abolished the antigonadotrophic effects of afternoon injections of methoxytryptophol. Similarly the antigonadotrophic effects of afternoon injections of melatonin, 5-methoxytryptophol and arginine vasotocin could be partially destroyed by 100 g and completely abolished by 1 mg melatonin administered in the morning.     

A special type of senile plaque,possibly an initial stage

Summary It is customary to distinguish primitive, classic and compact (burned out) senile plaques in Alzheimer's disease and senile dementia of the Alzheimer type (SDAT). Primitive plaques are characterized by altered neurites without accumulation of amyloid, classic plaques by an amyloid core surrounded by altered neurites and compact plaques by amyloid without pathological neurites. Here we describe a further type of plaque in which no amyloid or obviously altered neurites could be found by light microscopy with appropriate stains. This type of plaque was found mainly in the lateral entorhinal region and could be recognized by a slightly more intense staining and an altered texture of the neuropil in a spherical area having the same size as an early or mature plaque (100–150 m in diameter). In nonserial paraffin sections (3–4 m thick), a dark, silverpositive cell measuring 10–12 m in diameter was found in the center of 49 out of 400 such plaques (about 12%), which is the expected frequency if one assumes that every plaque contains such a cell and measures itself about 125 m. In fact, the reconstruction of 15 plaques (from four different patients) by means of serial sections demonstrated the presence of a central cell in each of them suggesting that this cell is an essential component of this plaque type. The central cell did not react with antibodies against cells of the mononuclear phagocyte lineage, such as alpha-1-antichymotrypsin, alpha-1-antitrypsin, leucocyte common antigen and lysozyme. However, it was consistently stained using the lectinRicinus communis agglutinin-1 (RCA-1), which is known to stain specifically microglia in the normal human brain. We assume that the type of plaque we describe might correspond to a very early step of plaque development and that they are possibly formed even before the primitive plaques mentioned above. We further suggest that such very early lesions might be caused by abnormal activity of microglial cells.     

Effect of parasympathetic blockade on the signalaveraged electrocardiogram

Low parasympathetic activity is associated with late potentials detected at a noise level of 0.4 V in a signal-averaged electrocardiogram (SAECG) following myocardial infarction. In contrast, at a noise level of 0.2 V, lowering parasympathetic activity influences late potential parameters in the opposite direction in healthy subjects. The aim of this study was to estimate the relationship between parasympathetic activity and the SAECG obtained at noise levels of 0.4 and 0.2 V in healthy subjects. Two SAECG recordings in 10 healthy subjects were obtained at noise levels of 0.2 and 0.4 V before and after parasympathetic blockade using atropine (1 mg). Signal-averaged QRS duration (SA-QRS), late potential duration (LPD) defined as duration of terminal signals below 40 V, and root mean square voltage of the terminal 40 ms of the averaged QRS (RMS₄₀) were measured. At a noise level of 0.2 V SA-QRS reduced from 124±14 to 114±17 ms (P=0.008), LPD from 37±10 to 28±14 ms (P=0.01), and RMS₄₀ increased from 26±22 to 41±25 V (P=0.006) during parasympathetic blockade compared to baseline values. At a noise level of 0.4 V the SA-QRS (115±15 ms) and LPD (29±11 ms) were lower and the RMS₄₀ (37±23 V) was higher compared to the noise level 0.2 V, and no systematic alterations of the three variables were found during parasympathetic blockade. The parasympathetic nervous system may induce a very low-amplitude late potential in the SAECG. The data suggest that parasympathetic activity and a low noise level may lead to a false late potential-positive SAECG in low arrhythmia risk subjects. Therefore, we recommend the use of a noise level of 0.4 V or identification of high arrhythmia risk patients by late potentialand low parasympathetic activity.     

B-HT 920 activates dopamine D2 receptors coupled to inhibition of adenylate cyclase activity

Summary In homogenates of female rat anterior pituitary, the azepine derivative B-HT 920 inhibited the forskolin-stimulated adenylate cyclase activity with an EC₅₀ value of 0.35 M. In male rat anterior pituitary, B-HT 920 curtailed the stimulation of adenylate cyclase activity by vasoactive intestinal peptide with an EC₅₀ of 0.20 M. In synaptic plasma membranes of rat striatum, B-HT 920 significantly reduced basal adenylate cyclase activity with an EC₅₀ of 0.68 M. Both in pituitary and striatum, the B-HT 920 inhibition was counteracted by the dopamine (DA) D₂ receptor antagonist 1-sulpiride, but not by the ₂-adrenergic antagonist yohimbine. These results indicate that B-HT 920 is capable of activating DA D₂ receptors negatively coupled to adenylate cyclase activity.     

Immunoglobulin heavy chain gene associations in myasthenia gravis: new evidence for disease heterogeneity

Summary Susceptibility to myasthenia gravis (MG) is known to involve genes residing in the major histocompatibility complex class I and II regions (HLA-B8 and DR3). Immunoglobulin heavy chain constant region (IgCH) allotypes have also shown some associations with MG. We have used restriction fragment length polymorphism analysis with probes to the IgCH switch (S) regions and 1 and the downstream marker D14S1 to investigate 189 Caucasoid patients with well-defined MG. A highly significant increase in the frequency of the 2.6 kilobase (kb) S homozygous genotype and the 2.6 kb S allele was found in patients with disease onset after the age of 40 years (late onset) compared with normal controls (P<0.00075 andP<0.025 respectively). No association was found at the S1 or D14S1 loci. In patients with an associated thymoma there was a moderate increase in the frequency of the 2.6 kb S and 7.4 kb S1 genotypes. These results independently support the previous separation of the late-onset subgroup. Finally, the stronger associations at S rather than at the downstream Sl, Gm and D14S1 loci suggest that the genes predisposing to MG are located within the variable region of the Ig heavy chain loci.     

Monoamine oxidase A-inhibiting components of urinary tribulin: purification and identification

Summary The endogenous monoamine oxidase (MAO) inhibitory activity, termed tribulin, contains several components. We have previously identified one of them, isatin, which is a selective inhibitor of MAO B. In the present study we have purified several further components of human urinary tribulin which act as selective inhibitors of MAO A. They have been identified by gas chromatography-mass spectrometry (GC-MS) as ethyl indole-3-acetate (and/or methyl indole-3-propionate), methyl indole-3-acetate and ethyl 4-hydroxyphenylacetate. IC₅₀ values for MAO A were found to be 44 M (105 M for methyl indole-3-propionate), 88 M and 120 M, respectively, whilst those for MAO B were each greater than 1 mM. The artificial formation of these esters was excluded by carrying the parent acids, from which they are presumably synthesized, through the purification procedure.As tribulin output is increased during stress or anxiety, these results point to a possible role for tryptamine and tyramine pathways in such disorders.     

Succinoxidase activity in reticular neurons of hyperactive rats

Summary The succinoxidase activity of single neurons from the reticular formation was measured with the Cartesian diver technique. The average activity of nerve cell bodies from the nucleus gigantocellularis or pontis caudalis from control rats was 4.5 l O₂×10^–4 per hour at 37°C. After rats had received --iminodipropionitrile, the succinoxidase activity of the same type neuron increased to an average of 8.0 l O₂×10^–4. It was suggested that this increase was of etiological significance for the symptoms of hyperactivity which developed later. Also when --iminodipropionitrile had been added to the reticular neurons from normal rats in vitro, the succinoxidase activity increased to 8.4 l O₂×10^–4 per hour.Supported by USPH Grant NB 1305.     

Intestinal neurohormones in protein-deficient rats

Summary The levels of noradrenaline, adrenaline, and serotonin in the jejunum and ileum of weanling rats fed protein-free (deficient) and high-protein (control) diets were analyzed. The concentration of noradrenaline of the deficient rats was markedly increased, both in the jejunum (0.430±0.039g/g vs. 0.188±0.019g/g in the control animals, +228%, P<0.001) and in the ileum (0.492±0.041g/g vs. 0.212±0.014g/g in the control rats, +232%, P<0.001). However, the levels of adrenaline and serotonin were unaltered in deficient rats as compared to controls, both in the jejunum (0.049±0.009g/g of adrenaline and 1.233±0.178g/g of serotonin vs. 0.047±0.006g/g of adrenaline and 1.364±0.131g/g of serotonin in the controls) and in the ileum (0.027±0.005g/g of adrenaline and 0.902±0.150g/g of serotonin vs. 0.038±0.006g/g of adrenaline and 1.118±0.192g/g of serotonin in the controls). In view of these results, it can be speculated that the abdominal distension and the reduced intestinal motility usually seen in the states of protein malnutrition could be caused, at least in part, by the accumulation of noradrenaline in the intestine.     

Untersuchungen des Plasma-Cortisols bei psychiatrischen Krankheitsgruppen

Zusammenfassung Bei 23 endogen Depressiven, 24 Schizophrenen, 15 Manikern, 23 depressiven Neurotikern, 23 nichtdepressiven Neurotikern und 29 nichtpsychiatrischen Patienten als Kontrollen wurde mit der Radioimmunassay-Methode der Plasma-Cortisol-Gehalt am Morgen (7.30 Uhr) und am Abend (19.30 Uhr) bestimmt. Der multiple Vergleich der Gruppenmittelwerte ergab folgende signifikante Unterschiede: In den Morgenwerten liegen die nichtdepressiven Neurotiker (¯x=16,6 g/100 ml), endogen Depressiven (¯x =14,8 g/100 ml) und depressiven Neurotiker (¯x=14,4 g/100 ml) höher als die Kontrollen (¯x=10,0 g/100 ml). In den Abendwerten liegen die nichtdepressiven Neurotiker (¯x=8,8 g/100 ml), Maniker (¯x=6,4 g/100 ml) und endogen Depressiven (¯x=7,0 g/100 ml) höher als die Kontrollen (¯x=3,6 g/ 100 ml), die nichtdepressiven Neurotiker (¯x=8,8 g/100 ml) außerdem höher als die depressiven Neurotiker (¯x=4,9 g/100 ml) und Schizophrenen (¯x= 4,4 g/100 ml).Die Ergebnisse werden mit der Literatur verglichen. Die Interpretation der Befunde ist problematisch: Neben krankheitsunspezifischen Streßfaktoren scheinen auch — zumindest bei endogener Depression — krankheitsspezifische Faktoren eine Rolle zu spielen.     

The effect of a 5-HT3 receptor antagonist,ondansetron, on brain stimulation reward,and its interaction with direct and indirect stimulants of central dopaminergic transmission

Summary 5-HT₃ receptors are abundant in central dopamine (DA) terminal areas. They do not affect basal DA turnover but appear to modulate DA release by e.g. morphine and nicotine. The interpretation of these findings is uncertain, and it is unclear whether 5-HT₃ receptors also influence the activity of compounds such as amphetamine and cocaine, which act more directly on the DA synapse. Variable-interval (VI), threshold-current hypothalamic self-stimulation can provide a continuous index of central dopaminergic activity, but is relatively insensitive to changes in 5-HT and thus offers a means of investigating this question. In the present study, a selective 5-HT₃ receptor antagonist, ondansetron (GR 38032F) (1.0 to 1000 g/kg sc), had no effect on VI self-stimulation, nor did a 100 g/kg dose affect facilitation of responding byd-amphetamine (500 jig/kg ip). Ondansetron (100 g/kg) reduced the initial depression of self-stimulation by high-dose nicotine (400 g/kg), but not the ensuing facilitation. Similar results were obtained in rats sensitized to nicotine by prior chronic exposure. These results support the proposal that 5-HT₃ receptors, normally quiescent under basal conditions, mediate the excitatory effect of compounds acting upstream from the DA neuron, such as nicotine, but do not affect the dopaminergic synapse directly.     

Apurulent bacterial meningitis (compartmental leucopenia in purulent meningitis)

Summary Meningococci and Haemophilus influenzae may invade the subarachnoid space during the bacteriaemic phase without impairment of the blood-CSF barrier and in the absence of any leucocyte reaction. In pneumococcal meningitis the CSF may also contain less than 100 cells/l despite the presence of pure bacterial cultures, but the barrier is completely broken when the serum/CSF concentration ratio is below 10. A clinical analysis of eight patients with fewer than 100 cells/l revealed that the first symptoms of meningitis appeared at least 3 days prior to the diagnostic lumbar puncture. There was a strong neutrophilic reaction in the blood with a prevalence of juvenile forms in most cases, indicating intact antibacterial defence mechanisms. Within 24 h after the start of antibiotic therapy the cell number rose above 2000/l accompanied by disappearance of pneumococci. Six of the eight patients died. In three cases autopsy revealed thick layers of pus over the convexities, indicating a compartmental separation of the ventricles and the spinal subarachnoid space. In one case of late diagnosed bacterial meningitis with a pleocytosis of 430/l the CSF lysozyme level was seven times higher than compatible with this cell number. Hyperphagocytosis and cellular disintegration is thought to cause the leucopenia within the spinal CSF compartment. Apurulent bacterial meningitis can be seen as a disease entity that is a diagnostic pitfall and also a prognostic sign.     

A Golgi study of the proximal portion of the human Purkinje cell axon

Summary The proximal portion of the Purkinje cell axon in normal cerebellum was investigated using the Golgi-Cox method. The axon emerging from the axon hillock tapered as it proceeded distally along the initial segment. The most distal portion of the initial segment was the narrowest (about 1 m). Then the axon became thicker again in the probable myelinated portion. The length of the axon hillock plus the initial segment ranged from 21 m to 52 m, 35±6 m on average ±SD. The axon arose from any site of the soma and the primary dendrite of the Purkinje cell. Almost half of the axons emanated from a lateral surface of the soma. The dendritic arbores of the Purkinje cell with a torpedo were atrophic.     

Effects of chronic treatment with methadone and naltrexone on sleep in addicts

Previous studies have described sleep disturbance secondary to chronic opiate use and abuse. Drug-dependency insomnia is of interest because chronic sleep disturbances can promote depressive symptoms which could lead to a drug relapse. For the first time we compared the polysomnographic parameters of 10 methadone-substituted outpatients and 10 naltrexone-treated outpatients. Methadone (-opioid agonist) produced a marked fragmentation of the sleep architecture with frequent awakenings and a decrease in EEG arousals. In comparison with methadone and controls, the naltrexone (-opioid antagonist) group showed the shortest sleep latency and the longest total sleep time. These data indicate that -agonists and -antagonists have different effects on sleep. The implications, especially the involvement of opioid-dopamine interactions on sleep and movements during sleep, are discussed.