C.-J. Estler

Modification by two beta-adrenergic blocking drugs of the effects of methamphetamine on behaviour and brain metabolism of mice

AN ANTAGONISTIC influence of propranolol on methamphetamine-induced excitation and the concomitant changes in brain metabolism has been reported (ESTLER and AMMON, 1967) but unfortunately propranolol has not only antiadrenergic j3-receptor blocking but also central depressant properties (ESTLER and AMMON, 1969; LESZKOVSKY and TARDOS, 1965; MURMANN, -ANTE and SACCANIGUELFI, 1966). Thus it could not be ruled out that the antagonism between propranolol and methamphetamine was a mere functional one. For this reason another adrenergic &receptor blocking drug, ~-(-)-(l-(4’-nitrophenyl)-2-isopropy~amino-ethano~ HCI) (INPEA) which is not only free of central depressant effects but has even central stimulant properties (MURMANN et nl., 1966; ESTLER unpublished) has been tested under the same experimental conditions. The combined effects of methamphetamine and the 8-adrenergic blocking drugs INPEA and propranolol on spontaneous motor activity and metabolites of the cerebral carbohydrate metabolism are described. Methamphetamine enhances motor activity and produces a decrease of the glycogen and an increase of the pyruvate content of the brain. INPEA and propranolol diminish the methamphetamine-induced motor excitation and prevent or reverse the changes in the cerebral glycogen and pyruvate contents produced by methamphetamine. It seems that glycogenolysis and-at least in part-central stimulation, too, have to be ascribed to the sympathomimetic properties of methamphetamine. The results are compared with those of our previous study with methamphetamine and propranolol (BTLER and AMMON, 1967).

Der Einfluß adrenerger β-Blockade auf die Wärmebildung bei akuter Kälteexposition

SummaryFor the investigation of the influence of the β-sympathicolytic agent propranolol on thermoregulation in white mice body temperature, oxygen consumption, glycogen, glucose, pyruvate and lactate in liver and skeletal muscle, and glucose, pyruvate, lactate and unesterified fatty acids in the blood were determined. Control animals exposed to an environmental temperature of 0°C showed a fall of the body temperature by only 3,6°, a rise of the oxygen consumption by 76%, a decrease of the glycogen content of liver and muscle, and an increase of the unesterified fatty acids in the serum. After pretreatment with propranolol oxygen consumption was not increased and the body temperature fell by 17.1°. The glycogen content of liver and muscle was not significantly diminished and the level of unesterified fatty acids in the serum was not raised. These results lead to the suggestion that β-sympathicolysis prevents the mobilization of carbohydrates and fat from the stores, which is necessary for the enhancement of metabolism and heat-production.ZusammenfassungAn weißen Mäusen wurde der Einfluß des β-Sympathicolyticums Propranolol auf die Wärmeregulation untersucht. Hierzu wurden Körpertemperatur, Sauerstoffverbrauch und der Gehalt von Leber und Muskulatur an Glykogen, Glucose, Pyruvat und Lactat sowie der Gehalt des Blutes an Glucose, Pyruvat, Lactat und unveresterten Fettsäuren bestimmt. Kontrolltiere zeigten bei Kälteexposition ein geringes Absinken der Körpertemperatur um 3,6°C, eine Steigerung des Sauerstoffverbrauchs um 76%, eine Abnahme des Glykogengehalts in Leber und Muskel und eine Zunahme der unveresterten Fettsäuren im Blut. Bei den mit Propranolol vorbehandelten Tieren kam es nach Kälteexposition zu keiner Zunahme des Sauerstoffverbrauchs, die Körpertemperatur nahm um 17,1°C ab. Die Abnahme des Glykogengehalts von Leber und Muskel und die Zunahme der unveresterten Fettsäuren im Serum fehlte. Es hat den Anschein, daß nach adrenerger β-Blockade die Kohlenhydrate und das Depotfett nicht mehr in ausreichender Menge mobilisiert und für eine vermehrte Wärmeproduktion genutzt werden können.

Ethanol-induced alterations in histamine content and release in the rat hypothalamus

SummaryIn the rat hypothalamus, histamine content and histidine decarboxylase activity are enhanced significantly after acute administration (80–160 mg/100g body weight) of ethanol. The effects are less pronounced after chronic treatment (15% v/v in drinking water for 4 weeks). Histamine methyltransferase is unaffected in either case. In hypothalamic slices preloaded with3H-histamine and superfused with amine free solution the basal and K+-induced efflux of3H-histamine are inhibited by alcohol. The inhibition of histamine release along with the increased levels of histamine may play an important role in the central effects of alcohol.

Der Einfluß von Kobaltgluconat und des Dikobaltsalzes der Äthylendiamintetraessigsäure (Co2EDTA) auf den Hirnstoffwechsel normaler und cyanidvergifteter Mäuse

ZusammenfassungAn weißen Mäusen wurde die cyanidantagonistische Wirkung von Kobaltgluconat und Co2-EDTA untersucht. 5 mg/kg Kobaltgluconat verhinderten sicher die äußeren Zeichen einer durch 1,75 mg/kg KCN i.v. hervorgerufenen Vergiftung. Die Schutzwirkung von 5 mg/kg Co2-EDTA war unsicherer. Durch beide Verbindungen wurde die durch KCN verursachte Steigerung der Glykolyse und die Einschränkung der Energieproduktion im Gehirn abgeschwächt, aber nicht völlig aufgehoben. Die Restitution des veränderten Metabolitgehalts wurde beschleunigt. Beide Kobaltverbindungen riefen keine äußerlich erkennbaren Vergiftungssymptome hervor, führten aber zu Änderungen im Metabolitgehalt des Gehirns, die für eine Einschränkung des Kohlenhydrat- und Energiestoffwechsels sprechen.

Prevention by pyrazole of ethanol-induced decrease of brain glycogen and coenzyme A

ETHANOL despite its central depressant properties causes changes in the metabolism of mouse brain that in some respects are exactly opposite to those caused by other central depressant agents, i.e. glycogenolysis (AMMON et al., 1965; ESTLEX & AMMON, 1965) and decrease of the acelylating capacity of coenzyme A (AMMON et al., 1965; RAWAT, 1974, SMYTH et al.: 1968, 1969). There is good evidence that the effect on brain coenzyme A is caused by acetaldehyde formed from ethanol rather than by ethanol itself (AMMON et al., 1967, 1969). The same may apply to ethanolinduced glycogenolysis in the brain. If this is true, prevention of the conversion of ethanol to acetaldehyde should also prevent the depletion of brain glycogen and coenzyme A. To test this hypothesis, the influence of ethanol on brain glycogen and coenzyme A was investigated in mice treated either with ethanol alone or with ethanol + pyrazole, which is a very potent inhibitor of alcohol dehydrogenase in liver and brain (GOLDBERG & RYDBERG, 1969; RASKIN & SOKOLOFF, 1972; THEOREJS. & YONETANI, 1963).

Überlebenszeit, Wiederbelebungszeit, Glykogen-, ATP- und Kreatinphosphatgehalt des asphyktischen Herzens unter dem Einfluß des Sympathicolyticums Propranolol

ZusammenfassungDie Blokkade sympathischerβ-Receptoren des Herzens durch Propranolol verhindert bei Mäusen die zu Beginn einer Asphyxie auftretende Steigerung der Herzfrequenz, verzögert den Abfall von Glykogen, ATP und Kreatinphosphat sowie den Anstieg des anorganischen Phosphats im asphyktischen Herzen und verlängert dosisabhängig die Überlebenszeit des asphyktischen Herzens.Im Gegensatz hierzu wird durch Propranolol die Erfolgsquote der Wiederbelebung des asphyktischen Herzens, d. h. die Wiederherstellung der normalen Herzfunktion durch Sauerstoffzufuhr, verschlechtert. Der sympathische Antrieb ist offenbar eine wichtige Voraussetzung für die Wiederbelebung anoxischer Herzen.Wir danken FräuleinI. Bödewadt, FräuleinM. Hausen und FräuleinB. Stahnke für ihre Mitarbeit bei den Versuchen. Den Firmen Boehringer-Ingelheim und Rhein-Pharma haben wir für Versuchsmengen von Flaxedil® und Dociton® zu danken.SummaryIf the sympathicβ-receptors in the hearts of white mice are blocked by propranolol the increase of heart rate in the beginning of asphyxia is prevented, the diminuation of the glycogen, ATP and phosphocreatine contents and the increase of orthophosphate are delayed, and the survival time of the heart is lengthened. On the other hand, the reanimation rate is reduced by propanolol. Therefore the sympathic stimulus seems to be a necessary condition for successful reanimation.

Effects of antagonists of adrenaline receptors and dopamine receptors on morphine-stimulated glycogen breakdown in mouse brain

M o K w i Y i . like some central stimulants reduces the glycogen content of the brain of mice by increasing cerebral glycogen breakdown (ESILE.R & AMMON. 1964: EsTLCR & MIILNI:GC,. 1971). By analogy with other central effects of morphine i t is assumed that this drug activates the glycogenolytic syctem indirectly but up to now there is no clear indication of the nature of the mediator involved. The present study was made in order to investigate whether or not drugs that block adrenaline receptors or dopamine receptors would inhibit the morphine-induced decrease of brain glycogen. This would indicate whether adrenaline receptors or dopamine receptors mediate the effect.

The influence of pyrazole on ethanol-induced changes in carbohydrate metabolism of the liver

SummaryThe effect of pretreatment with 340 μg/g pyrazole i.p., an inhibitor of alcohol dehydrogenase, on the changes in the carbohydrate metabolism of the liver, as produced by 4 mg/g ethanol i.v., was investigated in mice. Pyrazole completely prevented the ethanol-induced rise of the glycerol-1-phosphate content and of the glycerol-1-phosphate/dihydroxyacetone phosphate and lactate/pyruvate ratios and diminished the decrease of the hepatic pyruvate and lactate contents. This suggests, that these changes are mediated by shifts in the hepatic NADH/NAD ratio occurring during alcohol oxidation. The glycogen depleting effect of ethanol was not abolished by pyrazole showing that this effect is brought about—at least in part—by ethanol itself.