Role of 5-Hydroxytryptamine in Mental Diseases and its Antagonism to Lysergic Acid Derivatives

Cerletti, A; Rothlin, E

doi:10.1038/176785a0

Cited by 142 publications

(26 citation statements)

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“…This is in agreement with observations on the perfused lungs of cats (Gaddum, Hebb, Silver, and Swan, 1953) and of guinea-pigs (Bhattacharya, 1955), as well as in unanaesthetized guinea-pigs (Herxheimer, 1953b;. 1-Acetyl-LSD and 2-brom-LSD were about as potent as LSD in cats; they are also at least as active as LSD in inhibiting the effect of 5HT on the isolated rat uterus and on the isolated rat kidney (Cerletti and Rothlin, 1955;Cerletti and Konzett, 1956). Our results demonstrate that, under suitable conditions, those compounds which exhibit an anti-5HT action on plain muscle in vitro may act similarly in vivo.…”

Section: Discussionsupporting

confidence: 79%

The Effects of 5‐hydroxytryptamine and Its Antagonists on Tidal Air

Konzett¹

1956

British Journal of Pharmacology and Chemotherapy

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Various reports suggest that 5-hydroxytryptamine (5HT) can cause bronchoconstriction. Thus, Reid and Rand (1952) (Gaddum, Hebb, Silver, and Swan, 1953) and guinea-pig (Bhattacharya, 1955). A constrictor effect of 5HT has also been noted in the tracheal chain of the guineapig (Freyburger et al., 1952) and cat (Sinha and West, 1953). Furthermore, 5HT administered as an aerosol causes dyspnoea in the guinea-pig, resembling that produced by histamine or acetylcholine (Herxheimer, 1953a(Herxheimer, , 1953b(Herxheimer, , and 1955.As yet, the effect of 5HT on tidal air has not been investigated in the intact and spinal animal. It therefore seemed of interest to make such an investigation with a view to obtaining further information on the mode of action. Another purpose of the study was to investigate whether agents found to be potent antagonists of 5HT in isolated organs in vitro also antagonize the bronchoconstriction induced by SHT in vivo. METHODSCats were anaesthetized with a mixture of chloralose (0.05 g./kg.) and urethane (0.5 g./kg.) administered subcutaneously. In the course of some experiments first the vagi were cut and later the spinal cord was sectioned at C 1. Guinea-pigs were anaesthetized by intraperitoneal administration of urethane (1.2 g. /kg.). Spinal cats and guinea-pigs were also used, the operation being conducted under ether anaesthesia.

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Section: Discussionsupporting

confidence: 79%

The Effects of 5‐hydroxytryptamine and Its Antagonists on Tidal Air

Konzett¹

1956

British Journal of Pharmacology and Chemotherapy

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“…BrLSD resembles LSD in its antagonism to 5-HT, but differs from it in that it does not have the same psychological effects (Cerletti and Rothlin, 1955), and may even antagonize those of LSD (Ginzel and Mayer-Gross, 1956). It was therefore tested for its effects on substance P. When it was directly applied to guinea-pig ileum in concentrations up to 10-6, it neither increased nor decreased the response to substance P. When added to brain extract, it did not alter the effect of this extract on substance P. but when both LSD and BrLSD were present the inhibitory effect of LSD on the enzyme was prevented, so that substance P was inactivated.…”

Section: Resultsmentioning

confidence: 99%

The Preservation of Substance P by Lysergic Acid Diethylamide

Krivoy

1957

British Journal of Pharmacology and Chemotherapy

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Lysergic acid diethylamide (LSD) potentiated the response of guinea-pig ileum to substance P but not to histamine. It also inhibited the disappearance of substance P when incubated with guinea-pig brain extract but not when incubated with chymotrypsin. Eserine, morphine, mescaline, chlorpromazine, ergometrine, strychnine and 2 bromo-LSD did not have this effect. Oxytocin was not destroyed by brain extract. The inhibition of the destruction of substance P by LSD could be antagonized by 2 bromo-LSD. This effect of LSD may have some relation to its pharmacological actions.This paper concerns an evaluation of lysergic acid diethylamide (LSD) and various other drugs for their ability to inhibit the enzymatic destruction of substance P in vitro. The study was initiated when, during the course of an investigation of the contractile response of plain muscle to substance P, it was observed that LSD, in concentrations below (Fig. 1), potentiated the action of this polypeptide on guinea-pig ileum, whereas the action of histamine was not potentiated. Since Gullbring (1943) described an enzyme capable of destroying substance P at a fairly rapid rate, it seemed possible that the potentiation was due to the preservation of substance P from enzymatic destruction. METHODSAcetone-dried powders of guinea-pig brain were used as a source of the enzyme. The extract was found to be thermolabile, and consequently the powder was stored in a deep freeze until ready for use, at which time an aliquot was ground with Tyrode (1 to 2 mg. /ml.) and centrifuged for 2 hr. at 4' and 2,000 rev. /min. The optimal pH for activity of this enzyme was found to lie between 6 and 7 by the method described below. This fact suggested that this system was similar to that described by Gullbring.The substance P used in these experiments was prepared by Dr. T. B. B. Crawford of this laboratory. It was extracted from horse intestine by the method described by Amin, Crawford and Gaddum (1954), and contained 13 units/mg. Part of this was further purified by the method of Pernow (1953), and contained 60 units/mg. Experiments were conducted with both of these preparations.To test the potency of the brain extract and the modifications of its activity by pharmacological agents, the following mixture was prepared and incubated at 37'. Substance P (5 units/ml. in Tyrode) 0.5 ml.; 0.1 ml. of the brain extract supernatant; 0.1 ml. of the drug or drugs to be tested for inhibition of enzymatic activity, and Tyrode solution to make up 1.0 ml. In order to slow the reaction to a rate which could be measured accurately and to mitigate the disappearance of the LSD in the brain extract (Rothlin, 1956), the quantities of the brain extract were less than those used by Gullbring. After incubation the sample was cooled and an aliquot assayed on guinea-pig ileum in terms of a substance P standard in the presence of atropine 10'. Except where noted, drugs were applied to the guinea-pig ileum for bioassay purposes for a period of 30 sec. In certain experiments chymotrypsin (0.1 ml. o...

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“…Recent experiments (Blair, personal communication, 1955) indicate that its activity on the rat's uterus as an antagonist of HT is about 1/10 that of LSD. Ergometrine (2-2.5 mg./kg. intravenously) is known to cause sham rage in cats (Brown and Dale, 1935 (Cerletti and Rothlin, 1955 , and an attempt was therefore made to discover whether it also antagonizes the central action of HT in these cats. The dose was a large one.…”

Section: Resultsmentioning

confidence: 99%