Aaron Feldstein

The effect of para-chlorophenylalanine on the sleep of cats

1. 1. In this series of experiments we have shown that depletion of serotonin (5-HT) by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA) in cats is attended by a marked loss of sleep. 2. 2. Cats chronically supplied with electrodes to record the EEG, neck EMG and eye movements were contained and observed around the clock in screened, sound-attenuated rooms for up to 19 days. Their “vigilance profile” consisting of a three-level graph (PS = paradoxical sleep; SS = slow sleep; W = waking) was determined and total W-times, SS-times, and PS-times calculated for every 4 and 24 h periods. 3. 3. PCPA was administered in various doses i.p. A single dose of 200 mg/kg was sufficient to reduce sleep to close to zero level. The minimal sleep level occurred about 3 days after injection. Sleep was back, or close, to control level after about 16 days. With smaller doses, lesser sleep reductions were obtained. 4. 4. PS over total sleep ratio remained constant except for a relative increase of PS in those cases where total sleep approached zero level. 5. 5. 5-Hydroxytryptophan (5-HTP; 30 mg/kg i.p.) given 48 h after PCPA restored slow sleep temporarily to levels above control within 10 min after injection. PS started to occur about 5–6 h after 5-HTP. 6. 6. Biochemical analysis for 5-HT of the brains of cats treated with various doses of PCPA confirmed the observations in rats, mice and rabbits; various brain-stem and cortical areas were found to be markedly depleted of (total) 5-HT. 7. 7. It is suggested that discrepancies in the time course of sleep deprivation and total 5-HT content are due to such additional factors as negative feedback. Also, free 5-HT may show time courses of depletion and restoration different from those of total 5-HT.

The effect of ethanol ingestion on serotonin-C14 metabolism in man.

Abstract Low doses of ethanol ingested prior to serotonin-C 14 in man significantly decreased formation of urinary 5-HIAA-C 14 . The decreased formation of 5-HIAA-C 14 was dependent upon the dose and time of administration of ethanol and was related to the blood alcohol level. It was suggested that ethanol increased NADH and decreased NAD such that 5-hydroxyindoleacetaldehyde-C 14 derived from the serotonin-C 14 was preferentially converted to 5-hydroxytryptophol-C 14 with a concomitant decrease in 5-HIAA-C 14 .

Tryptophol, 5-hydroxytryptophol and 5-methoxytryptophol induced sleep in mice

Abstract Tryptophol, 5-hydroxytryptophol and 5-methoxytryptophol were found to induce sleep in mice. The onset of action was most rapid for tryptophol and 5-methoxytryptophol; 5-hydroxytryptophol had the slowest onset, probably due to difficulty of transport across the blood-brain barrier. Sleep times were shortest for tryptophol and 5-methoxytryptophol and longest for 5-hydroxytryptophol. It was suggested that the tryptophols or the corresponding aldehydes may play a role in physiological sleep mechanisms.

Enzymatic conversion of serotonin to 5-hydroxytryptophol

Abstract The metabolism of serotonin-C 14 in rat liver homogenate was shown to produce 5-hydroxyindoleacetaldehyde, 5-hydroxytryptophol, and 5-HIAA. The addition of nicotinamide and NAD, coenzyme of aldehyde dehydrogenase, to the incubation mixture increased the rate of formation of 5-HIAA with a concomitant decrease in the remaining 5-hydroxyindoleacetaldehyde. The addition of NADH, coenzyme for alcohol dehydrogenase, increased the rate of formation of 5-hydroxytryptophol with a concomitant decrease in the remaining 5-hydroxyindoleacetaldehyde and 5-HIAA.

Effect of Ethanol on Neurohumoral Amine Metabolism

This review covers the interaction of ethanol with the neurohumoral amine substances: serotonin, norepinephrine, acetylcholine, and γ-aminobutyric acid. Brodie and co-workers (Brodie and Shore, 1959; Brodie et al., 1959) have proposed that serotonin and norepinephrine are neurotransmitters in the central nervous system, where serotonin mediated the trophotropic system involving decreased psychomotor activity, drowsiness, sleep, etc., and norepinephrine mediates the ergotrophic system involving alertness, increased psychomotor activity, etc. Acetylcholine (Karczmar, 1969; Koelle, 1969) and GABA (Elliot and Jasper, 1959; Roberts and Kuriyama, 1968) have also been considered as synaptic transmitters in the central nervous system. The role of these substances, whether synaptic transmitters or regulators of neuronal activity, is controversial. Although the major emphasis in this review is on the brain and the central nervous system, the interaction of ethanol with the neurohumors in peripheral tissues has been covered.

The effect of ethanol on the in vivo conversion of 5-HTP-14C to serotonin-14C, 5-hydroxyindoleacetaldehyde-14C and its metabolites in rat brain.

Ethanol was administered i.p, to rats 1 hr prior to sacrifice and 5-HTP-14C was administered i.p. 30 min prior to sacrifice. Multiple doses of ethanol increased 5-HTP-14C found in the brain, possibly due to decreased efflux. Multiple doses of ethanol also increased the ratio of 5-hydroxyindoleacetaldehyde and/or 5-hydroxytryptophol to 5-HIAA. The possibility was considered that the increased neutral fraction and decreased acid fraction was due to inhibition of aldehyde dehydrogenase and activation of alcohol dehydrogenase by virtue of an ethanol-induced increase in brain NADPH/NADP ratio. High doses of ethanol, 6 lg/kg, slightly inhibited decar☐ylase and monoamine oxidase. The possibility was considered that inhibition of decar☐ylase and monoamine oxidase was due to acetaldehyde derived from ethanol

Pyrazole and ethanol potentiation of tryptophol-induced sleep in mice.

Abstract It was previously reported that tryptophol, 5-hydroxytryptophol and 5-methoxytryptophol induced sleep in mice, rats and cats. Evidence was presented in this report that both ethanol and pyrazole markedly potentiate tryptophol-induced sleep in mice. It was suggested that endogenous tryptophols and/or their corresponding aldehydes may play a role in physiological and drug-induced sleep.

The effect of ethanol and disulfiram on serotonin-14C metabolism in rat liver homogenates

Abstract A study was made of serotonin-14C metabolism in rat liver homogenates with and without exogenous NAD and NADH. Serotonin was converted to 5-hydroxy-indoleacetaldehyde by MAO; neither ethanol nor disulfiram inhibited MAO. The aldehyde was converted to 5-hydroxytryptophol by the NADH-linked alcohol dehydrogenase; neither ethanol nor disulfiram inhibited alcohol dehydrogenase. The 5-hydroxyindoleacetaldehyde was converted to 5-HIAA by the NAD-linked aldehyde dehydrogenase. Ethanol decreased 5-hydroxyindoleacetaldehyde with a concomitant increase in 5-hydroxytryptophol and decrease in 5-HIAA. Disulfiram increased 5-hydroxyindoleacetaldehyde with a concomitant increase in 5-hydroxytryptophol and decrease in 5-HIAA.

Serotonin Metabolism in Pineal Homogenates

Publisher Summary The conversion of 5-HT to 5-methoxytryptamine in pineal and subsequent metabolic transformations to 5-methoxyindoleacetic acid and 5-methoxy tryptophol is in vivo metabolic pathway. The analogous pathway from 5-HT to 5-HIAA in pineal homogenates is demonstrated in this chapter. 5-Methoxytryptophol is isolated from pineal. The analogous pathway from 5-HT to 5-hydroxytryptophol by way of alcohol dehydrogenase predominates if NADPH2 is added to the pineal homogenates. It has now been established that 5-hydroxyindoleacetaldehyde may be metabolized not only to 5-hydroxyindoleacetic acid and 5-hydroxytryptophol but also to 5-hydroxyindolecarboxaldehyde and the corresponding 5-hydroxyindolecarboxylic acid. Further work is essential to validate this pathway both in vitro and in vivo.

Phenelzine-induced convulsions and alterations in the conversion of 5-HTP-14C TO serotonin-14C in vivo

Abstract A method was developed for the analyses of 5-hydroxytrptophan (5-HTP), serotonin, 5-hydroxyindoleacetic acid, and neutrals in rat brain after intraperitoneal injection of 5-HTP- 14 C. Phenelzine altered the metabolism of 5-HTP- 14 C by inhibition of monoamine oxidase and decarboxylase. The occurrence of convulsions as the dose of phenelyine was increased did not correlate with decarboxylase inhibition.