The anticonvulsant action of L-2,4-diaminobutyric acid. The GABA uptake inhibitor, L-2,4-diaminobutyric acid (L-DABA) was examined for potential anticonvulsant activity in mice. Given intracerebroventricularly (i.c.v., 2 mumoles) L-DABA almost doubled the CD50 of picrotoxin and 3-mercaptopropionate (3-MP), a glutamate decarboxylase inhibitor--the convulsants being administered 15 min after the L-DABA. The anticonvulsant effect was not observed after 40 min. L-DABA given i.p (5 mmoles/kg) was also anticonvulsant against 3-MP but given i.p. or i.c.v. had no anticonvulsant action against strychnine. The D-isomer of DABA, less active as an inhibitor of GABA uptake, had no anticonvulsant activity against 3-MP and nor did three other inhibitors of GABA uptake, namely nipecotic acid, cis-1,3-aminocyclohexane carboxylic acid (ACHA) and beta-alanine. Possible mechanisms of the anticonvulsant action of L-DABA are discussed.


Antagonism of cholinomimetics by troxypyrrolidinium in guinea-pig atria and longitudinal ileal muscle: comparison with hemicholinium-3. The inhibitory effect of troxypyrrolidinium (trox) (10(-6) to 2 x 10(-3) M) on responses to carbachol (CCh) and acetylcholine (ACh) was investigated in the electrically stimulated left atrium and longitudinal ileal muscle of the guinea pig. In both tissues, trox exhibited antimuscarinic activity causing parallel shifts of the concentration--response curves to both agonists with no depression of maximum responses. Responses to CCh were inhibited by trox (5 x 10(-4) M) to a greater extent than responses to ACh and this difference was maintained following inhibition of cholinesterases with dyflos. In the guinea-pig atrium using CCh as agonist dose ratios produced by the higher concentrations of trox (greater than 5 x 10(-5) M) were less than expected resulting in a non-linear Arunlakshana--Schild (A-S) plot and this effect of trox was maintained in the presence of mecamylamine (2 x 10(-5) M). In longitudinal ileal muscle flattening of the A-S plot with high concentrations of trox did not occur. Although hemicholinium-3 (HC-3) produces a non-linear A-S plot for antimuscarinic activity in atria the A-S plot obtained with the longitudinal ileal strip using HC-3 (2 x 10(-5) to 2 x 10(-3) M) did not exhibit flattening at high concentrations. The dose ratios obtained with HC-3 (5 x 10(-4) M) using CCh as agonist were significantly greater than those obtained with ACh. It is suggested that trox, like HC-3, acts as a metaffinoid antagonist at the muscarinic receptor.


Effects of anaesthetics and anticonvulsants on the action of kainic acid in the rat hippocampus. The effects of anaesthetics and anticonvulsants on the acute behavioral response and neurochemical alterations following intrahippocampal injection of kainic acid were examined. When compared to the effects in animals anaesthetized with a combination of chloral hydrate and pentobarbital (Equithesin), brief anaesthesia with ether or with hexobarbital potentiated whereas prolonged anaesthetia attenuated the action of 0.5 microgram of kainic acid. Of the constituents of Equithesin, chloral hydrate offered less protection than pentobarbital. The anticonvulsants, phenobarbital, diazepam, diphenylhydantoin, and carbamazepine offered partial protection when administered in conjunction with ether anaesthetia.


Morphine analgesia and the bulbospinal serotonergic system: increase in concentration of 5-hydroxyindoleacetic acid in the rat spinal cord with analgesics. Administration of an analgesic dose of morphine increased the concentration of the metabolite of 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (5HIAA), in the spinal cord of rats. The time course of the change in 5HIAA concentration in the dorsal half of the spinal cord corresponded to that of the morphine analgesia, while such was not the case in the ventral half. When the spinal cord was transected at C1, the effect of morphine on 5HIAA concentration disappeared. After transection at the inter-collicular level, this effect remained. The possible relationship between morphine analgesia and descending serotonergic neurons in the spinal cord is discussed.


Effects of an anabolic steroid and vitamin B complex upon myopathy induced by corticosteroids. In rats repeatedly treated with dexamethasone, body weight decreased severely, creatine content in urine increased, tetanic contraction of the gastrocnemius muscle decayed easily and twitch tension of the muscle had a slow rise time. In a group of rats given large doses of vitamin B complex along with the anabolic steroid, nandrolone phenylproprionate, all syndromes described above for the dexamethasone-treated rats were prevented, dose dependently by vitamin B complex. The individual components of the vitamin B preparation combined with the nandrolone phenylpropionate partially suppressed the changes induced by dexamethasone. Diphenylhydantoin depressed the slow rise time of twitch tension as effectively as did vitamin B complex with nandrolone phenylpropionate. From the results presented here and facts previously reported it was concluded that the condition of the animals could be well controlled by repeated administration of vitamin B complex with nandrolone phenylpropionate, even though dexamethasone was repeatedly injected.


Distribution and localization of p-hydroxy-d-amphetamine in rat brain. p-Hydroxy-d-amphetamine (p-OHdA) penetrates the blood--brain barrier poorly, when given acutely or by repeated systemic treatments, or when formed by biotransformation from administered d-amphetamine. However its distribution is relatively selective as it accumulates in the striatum more than in the brainstem. The rate of disappearance also differs in the two areas, being slower in the striatum than in the brainstem. These findings suggest that p-OHdA might be stored in different compartments. To check whether p-OHdA specificially accumulated in nerve terminals, catecholaminergic nerve endings were destroyed with 6-hydroxydopamine (6-OHDA). It has been shown that p-HOdA accumulates much less in the striatum of 6-OHDA-treated rats than of controls. This effect was not present in the brainstem. Accumulation of p-OHdA was similar after repeated d-amphetamine administration. The results are interpreted as showing that p-OHdA tends to accumulate in dopaminergic structures.


Effects of viloxazine, its optical isomers and its major metabolites on biogenic amine uptake mechanisms in vitro and in vivo. Viloxazine hydrochloride (ICI 58,834, VIVALAN) a chemically novel antidepressant, shows selective inhibition of noradrenaline uptake into mouse heart in vivo and into rat brain in vitro. The noradrenaline uptake inhibitory activity resides primarily in one of the two optically active isomers, and it is suggested that in the conformation adopted for uptake by noradrenaline, the aryl and the amino groups are trans. In a comparison of in vivo and in vitro potency, tri- and tetracyclic antidepressants exhibit a good correlation. However, viloxazine possesses higher in vivo activity than would be expected from in vitro studies. The latter finding cannot be readily explained on the basis of known pharmacokinetic or metabolic factors.


Angiotensin II mediation of adrenal catecholamine secretion induced by intrarenal isoprenaline infusion. Isoprenaline infusion into the renal artery of the cat induced an increase in the catecholamine (CA) secretion rate from the adrenal gland. CA release by isoprenaline was preferentially noradrenaline. Intravenous infusion of an angiotensin II (A II) antagonist abolished adrenal CA response to intrarenal isoprenaline injection. It is suggested that intrarenal isoprenaline infusion stimulates renal renin release and A II production which, in turn, stimulates adrenal CA secretion.


Chronic effects of 6-hydroxydopamine and reserpine on myocardial adenylate cyclase. The effects of chronic administration of 6-hydroxydopamine or reserpine on catecholamine-sensitive adenylate cyclase from rat hearts were studied. Not only basal adenylate cyclase activity, but stimulation of the enzyme by norepinephrine, isoproterenol, NaF, guanylyl-imidodiphosphate, or combination of isoproterenol and guanylyl-imidodiphosphate, was significantly increased in the treated than in the control hearts. It is inferred that supersensitivity of myocardial adenylate cyclase following chronic treatment with reserpine or 6-hydroxydopamine may result from an increase in the catalytic activity of the enzyme.