L. György

Study on the excitation induced by amphetamine, cocaine and alpha-methyltryptamine.

SummaryAtropine and benactyzine enhance the hypermotility produced by amphetamine and cocaine, but diminish the hypermotility caused by α-methyltryptamine. Tremorine decreases amphetamine hypermotility. Methylsergide increases hypermotility produced by amphetamine and does not influence the effect of cocaine and α-methyltryptamine. Chlorpromazine and phenoxybenzamine diminish hypermotility produced by all the three excitants.Reserpine inhibits the effect of cocaine and α-methyltryptamine and does not influence that of amphetamine.Prenylamine diminishes the effect of amphetamine, cocaine and methyltryptamine.The possible significance of these findings is discussed.

Some central nervous properties of diethyldithiocarbamate

SIR,-Diethyldithiocarbamate has been shown to inhibit dopamine p-oxidase in the ileum of rats and rabbits, so that 20&500mg/kg of the compound decreases the noradrenaline content and increases the dopamine level (Collins, 1961). Carlsson, Lindquist, Fuxe & Hokfelt (1966) confirmed the noradrenalinedecreasing effect in rat ileum, heart and brain and demonstrated an increase of dopamine level in the brain stem and in the hemispheres ; but no difference was found in the striatum or in the whole brain. We find that diethyldithiocarbamate has certain depressing effects on the central nervous system. After the intravenous administration of 50 mg/kg of hexobarbitone the sleeping time in control mice was 429 sec f129 (s.d.) When the animals were given diethyldithiocarbamate, 400 mg/kg, 2 hr before the experiment the sleeping time increased to 2478 sec f746 (s.d.). The compound had no effect on tremorine-induced tremor in mice and it was also ineffective towards amphetamine toxicity in aggregated mice.

The interaction of hemicholinium-3 and oxotremorine in isolated organ preparations.

On isolated ileum preparations of the rat and guinea‐pig, hemicholinium‐3 antagonizes contractions elicited by acetylcholine and oxotremorine to the same extent. Hemicholinium‐3 was a mild antagonist to acetylcholine but a stronger one to oxotremorine and carbachol on the ileum of the rabbit. Whereas hemicholinium‐3 has no anti‐acetylcholine activity on the isolated urinary bladder of the rat, it antagonizes the contractions elicited by oxotremorine and carbachol, and acetylcholine after eserine. Morphine has an anti‐oxotremorine activity on this organ. Increasing concentrations of oxotremorine release increasing amounts of acetylcholine from the rat isolated intestine.

Evidence that serotonin receptors are involved in the anticonvulsant effect of yohimbine in mice

The threshold of seizures induced by electroconvulsive shock (ECS) was determined in mice and the effects of α2-adrenoceptor antagonists (yohimbine, rauwolscine, idazoxan), α2-adrenoceptor agonists (clonidine, B-HT 920), serotonin antagonists (methysergide, metergoline) and a serotonin agonist (quipazine) were studied. The interaction of yohimbine with clonidine, methysergide, metergoline and quipazine was also examined. It was found that yohimbine and rauwolscine elevated the seizure threshold, while idazoxan was ineffective. Clonidine and B-HT 920 were also ineffective, but quipazine elevated the seizure threshold. Methysergide and metergoline did not change the seizure threshold alone, but both of them antagonized the anticonvulsant effect of yohimbine. Clonidine failed to antagonize yohimbines effects. Quipazine potentiated yohimbines action. These results suggest that, in mice, the protective effect of yohimbine against ECS-induced seizures may be mediated via serotonin receptors and not via α2-adrenoceptors.

Pulmonary hypertensive and other haemodynamic effects of capsaicin in the cat

Abstract The effect on systemic arterial pressure, pulse rate, central venous pressure, heart contractile force, and pulmonary arterial pressure of capsaicin administered intravenously and into the left atrium of anesthetized open chest cats was investigated. Intravenous administration of capsaicin causes an elevation of the systemic arterial pressure often preceded by a fall, sometimes leading to the death of the animal. Following left atrial administration a pressor response could invariably be observed. Capsaicin causes a decrease in the heart contractile force. This effect is more marked after intracardial than after intravenous administration. Capsaicin causes a strong increase of the pulmonary arterial pressure. The reaction is rapid in onset and is followed by a second pressor phase. Histamine, bradykinin, serotonin, adrenaline and nor-adrenaline differ from capsaicin in the intensity and time of onset of the increase in pulmonary arterial pressure. It is concluded that pulmonary vasoconstriction probably plays an important role in the blood pressure fall caused by lethal doses of capsaicin.

Modification of certain central nervous effects of haloperidol during long-term treatment in the mouse and rat.

SummaryThe chronic administration of haloperidol to mice over periods of 1 week to 3 weeks has been shown not to decrease the anti-amphetamine properties of the compound, as measured by determining group toxicity and the inhibition of enhanced metabolic rate; on the other hand, the cataleptogenic effect of the drug slightly and transiently decreased after long-term treatment, the potentiation of pentobarbital narcosis being markedly reduced.In rats, prolonged administration of haloperidol for 2 to 3 months failed to affect cataleptogenic activity, diminished the potentiating effect on pentobarbital narcosis, and had no influence on the inhibition of amphetamine-induced stereotypy. The inhibition of amphetamine hypermotility, however, exhibited a considerably altered pattern, developing much more slowly but increasing gradually.The chronic administration of haloperidol has been shown to have no effect on brain noradrenaline and dopamine levels in either the mouse or the rat.

The subcellular distribution of (+)‐amphetamine and (±)‐p‐chloroamphetamine in the rat brain as influenced by reserpine

Amphetamine and its p-chloro derivative, p-chloroamphetamine have some common pharmacological actions. Both produce hypermotility in mice (Pfeifer, Gyorgy & Fodor, 1968) ; p-chloroamphetamine is somewhat less effective than amphetamine. Amphetamine increases the basal metabolism of rats and mice and this effect has a central origin (Tssekutz & Gyermek, 1949; Pfeifer, Vizi & others, 1964). p-Chloroamphetamine also increases metabolism in rats and mice (Pfeifer, unpublished). Amphetamine hypermotility occurs in the presence of reserpine, while that of p-chloroamphetamine is inhibited by reserpine (Pfeifer & others, 1968). Amphetamine slightly decreases brain noradrenaline (McLean & McCartney, 1961 ; Sanan & Vogt, 1962) and does not influence the brain level of 5-hydroxytryptamine ( ~ H T ) whereas p-chloroamphetamine decreases brain ~ H T levels considerably without influencing the noradrenaline content of the brain (Pletscher, Bartholini & others, 1964; Fuller, Hines & Mills, 1965). It is supposed that amphetamine may act by releasing extra-granular catecholamines (Carlsson, Lindqvist & others, 1966) and in large doses it has a direct releasing effect on the amine storing granules (Lundborg, 1969). The aim of the present work was to see if studies on subcellular distribution of amphetamine and its p-chloro-derivative in the brain could further elucidate their mode of action. C.F.E. albino rats (120-150 g) were given 5 mg/kg of (+)-amphetamine sulphate together with 10 IIC~[~H]-( +)-amphetamine or 15 mg/kg of (&)-p-chloroamphetamine intraperitoneally 30 or 60 min, respectively before decapitation. Reserpine was administered 43 h before. Amphetamine was determined by the liquid scintillation method with a four channel Packard instrument after extraction according to Axelrod (1954). 1954). p-Chloroamphetamine was determined spectrophotometrically (Axelrod,

Studies on the potentiation of the antinociceptive effect of oxotremorine by tetrabenazine in mice

The antinociceptive effect of Oxotremorine in mice was increased by tetrabenazine in the hot plate test. This effect of tetrabenazine was antagonized by desmethylimipramine and amphetamine, and enhanced by 5-hydroxytryptophan.Pretreatment with tetrabenazine prevented the increase in the level of acetylcholine in the brain induced by oxotremorine. There was no correlation between the antinociceptive effect and the acetylcholine concentration in the brain in animals treated with oxotremorine.It is suggested that in the enhancement of the antinociceptive effect of oxotremorine caused by tetrabenazine the depletion of catecholamines and not that of serotonin plays a predominant role.

Central cholinergic interactions in somato-vegetative reflexes

Abstract In cats lightly anaesthetized with urethane (600 mg/kg, i.p.), electrical stimulation of the sciatic nerve elicited frequency-dependent pressor reflexes and contractions of the nictitating membrane. Administration of oxotremorine (0.2 mg/kg, i.v.) or physostigmine (0.5 mg/kg, i.p.) resulted in depression of the pressor reflexes. At the same time, physostigmine enhanced the reflex contractions of the nictitating membrane, while oxotremorine induced sustained contraction of the latter. All these effects were antagonized by the tertiary amine scopolamine, but not by the quaternary atropine methylbromi. The results point to a role of central cholinergic mechanisms in the integration of somato-vegetative reflexes, and give evidence that the sympathetic driving of different effectors is not uniformly organized by the central nervous system.

Oxotremorine: acute tolerence to it and its central “cholinolytic” effect in mice

Decsi, VSlrszegi & MChes (1961a, b) reported that tremorine lost much of its analgesic, tremorigenic and narcosis-potentiating properties when given to mice. Keranen, Zaratzian & Coleman (1961) observed a progressive decline of the compound’s tremorigenic effect after chronic treatment of unstated duration. Oelszner (1965) was unable to corroborate the observation on the analgesic effect of tremorine made by Decsi & others. Doses of tremorine and oxotremorine prevent albino mice from clinging for more than 3 to 6 s to a rod operated at 7 rotations/min. Activity was regarded as negative in experiments in which the animal held fast to the rotarod for at least 180 s. The doses given are for oxotremorine oxalate, physostigmine salicylate, nicotine hydrogen tartrate, and tremorine dichlorhydrate. Table 1 shows that a first injection of tremorine reduces the rotarod activity of a second injection given 16 h later, and totally prevents that of oxotremorine. The rotarod activity of oxotremorine (0.5-1.0 mg/kg, i.p.) wears off within 60-90 min.