Walter Lovenberg

In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain

A single high dose of methylenedioxymethamphetamine, a psychedelic agent, produced a rapid and persistent depletion of striatal indoles similar to that observed following administration of the serotonergic neurotoxin p-chloroamphetamine. The drug had little effect on dopaminergic variables. Like p-chloroamphetamine, methylenedioxymethamphetamine was found to be a relatively selective agent for inducing [3H]serotonin release in vitro. The serotonin uptake inhibitor, citalopram, blocked both [3H]serotonin release in vitro and striatal serotonin depletion in vivo, indicating that both processes were carrier dependent. In vivo comparisons of the stereoisomers of methylenedioxymethamphetamine indicated two phases of serotonin depletion similar to those reported for p-chloroamphetamine. Although both the (+)- and (-)-stereoisomers produced an acute (3 hr) decrease in striatal indoles, the long-term effects of the drug showed stereoselectivity in that the (+)-enantiomer produced the most dramatic serotonin depletion. Comparison of the effects of the stereoisomers of methylenedioxymethamphetamine and its n-desmethyl analog, methylenedioxyamphetamine, on [3H]serotonin and [3H]dopamine release in vitro showed the (+)-enantiomer of both drugs to be the more potent releasing agent. In spite of its reported lack of hallucinogenic activity, (+)methylenedioxyamphetamine was found to be of a potency similar to that of (+)methylenedioxymethamphetamine in inducing [3H]serotonin release in vitro. The results are discussed in terms of the neurochemical similarities between methylenedioxymethamphetamine and p-chloroamphetamine as well as the proposed role of serotonin release in the behavioral effects of methylenedioxymethamphetamine.

Effects of drugs on human blood platelet and plasma amine oxidase activity in vitro and in vivo.

Abstract A method employing radioactive substrates has permitted sensitive assay of monoamine oxidase (MAO) activity in blood platelets and plasma. Kinetic studies indicate that while platelet and plasma MAO are distinct from that of liver mitochondria, the platelet and liver enzymes are quite similar, particularly in the characteristics of their response to inhibitors. Administration of six different MAO inhibitors including furazolidone to human subjects resulted in marked inhibition of platelet MAO, accompanied by expected changes in urinary tryptamine excretion. Effects of these drugs on plasma MAO were variable; an additional drug, isoniazid, in therapeutic dose was found to inhibit markedly plasma, but not platelet, MAO. Use of platelet MAO assay in the direct assessment of the MAO-inhibitory potency of drugs in man is suggested.

Effects of Dietary Sodium and of Acute Saline Infusion on the Interrelationship between Dopamine Excretion and Adrenergic Activity in Man

The effects of dietary sodium and of saline infusion on urinary dopamine and norepinephrine and on the relationship of these catecholamines to adrenergic activity were determined. In seven normal subjects on a 9-meq sodium intake, urinary dopamine and norepinephrine were 136+/-18 (SE) and 37.4+/-5.3 mug/day, respectively. When sodium intake was increased to 209 or 259 meq/day, urinary dopamine increased to 195+/-20 mug/day (P<0.01) whereas urinary norepinephrine decreased to 21.1+/-3.0 mug/day (P<0.01). Infusion of saline in seven subjects increased sodium excretion and urinary dopamine (from 2.18+/-0.22 to 2.79+/-0.19 mug/20 min, P<0.01), but decreased plasma dopamine-beta-hydroxylase by 33% and urinary norepinephrine insignificantly. The clearance of inulin and p-aminohippurate did not change significantly and filtration fraction was the same. The data indicate that an increase in dietary sodium or infusion of saline results in an apparent decrease in adrenergic activity and an increase in urinary dopamine. Dopamine excretion would thus appear to relate inversely to adrenergic activity and to parallel sodium excretion. These findings suggest a possible role for dopamine and norepinephrine in the regulation of renal sodium excretion.

Review of the role of the central serotonergic neuronal system in blood pressure regulation.

SUMMARY Alterations in the dynamics of brain serotonin biosynthesis can lead to changes in cardiovascular function. It appears that the activation of cerebral serotonin receptors produces a pressor effect in normotensive rats but produces a depressor effect in nonnotensive cats or dogs. On the other hand, reductions in the levels of serotonin can prevent the onset of hypertension in some experimental hypertensive models and lower the blood pressure of organisms with established hypertension. The ability of brain serotonin to modulate arterial blood pressure may be mediated by the influences of the serotonergic neuronal systems on efferent sympathetic activity. Finally, the reduction in sympathetic outflow produced by increasing brain serotonin levels in dogs protects the heart against ventricular fibrillation and may, therefore, constitute a reasonable adjunct in the management of high-risk, cardiac-arrest patients.

Further studies on tryptophan hydroxylase in rat brainstem and beef pineal

Abstract Soluble tryptophan hydroxylating enzymes have been obtained from both the beef pineal gland and rat brainstem. The enzymes have a pH optimum of 7.5 and appear to be typical aromatic ring hydroxylases. Although aniron requirement of the enzymes can be demonstrated by iron chelators, exogenous iron is not absolutely required for activity. Tetrahydrobiopterin was more effective than 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8 tetrahydropteridine as a cofactor for the enzymes. The beef pineal enzyme hydroxylates phenylalanine at approximately the same rate as it does tryptophan, whereas the brain enzyme showed no detectable activity toward phenylalanine. Finally, catechol compounds are effective inhibitors of the enzymes, presumably because of their ability to chelate iron.

Methylenedioxymethamphetamine: A potentially neurotoxic amphetamine analogue

The amphetamine analogue, methylenedioxymethamphetamine (MDMA) has received considerable attention recently as a novel and increasingly popular psychoactive agent. When administered acutely to rats in high doses, MDMA caused a selective and dramatic decrease in brain concentrations of serotonin and its metabolite, 5-hydroxyindoleacetic acid. The depletion of serotonin and its metabolite persisted for up to at least one week after a single injection of MDMA at approximately four to five times the acute dose reported for humans. These results are discussed in terms of the possible neurotoxic effects of MDMA.

Physiologically active amines in common fruits and vegetables

Abstract 5-Hydroxytryptamine, tryptamine, tyramine, 3,4-dihydroxyphenylethylamine and norepinephrine have been identified and assayed in a large number of fruits and vegetables. The significance of these findings with respect to plant physiology and to dietary effects in animals is discussed.

Tryptophan Hydroxylation in Mammalian Systems

Publisher Summary The development of a quantitative assay system and appropriate assay conditions for mammalian tryptophan hydroxylase has permitted a preliminary characterization of this enzyme. Tryptophan hydroxylase from brainstem and pineal tissue is either soluble or easily solubilized from mitochondrial fraction and exhibits the characteristics of a typical aromatic ring hydroxylase. This rate-limiting enzyme is extremely useful in understanding the hydroxyindole pathway of tryptophan metabolism and eventually the role of 5-HT in tissues. Hydroxylation of tryptophan at the 5-position is the first step in the hydroxyindole pathway of tryptophan metabolism. This pathway leads to the formation of physiologically active substances such as 5-HT and melatonin. The tryptophan hydroxylating enzyme activity shows complete dependence on the presence of oxygen, a reduced pteridine, and ferrous iron. Relatively high levels of 2-mercaptoethanol (0.05 M) are also required for optimal in vitro enzyme activity. With the availability of this reproducible source of tryptophan hydroxylating enzyme, it has been possible to develop a sensitive radioassay, which now has been successfully applied to normal mammalian tissues.

Norepinephrine Metabolism in Brainstem of Spontaneously Hypertensive Rats

Concentrations of norepinephrine in lower brainstem and hypothalamus of genetically hypertensive rats are significantly lower than in control rats. There is a concomitant reduction (50 percent) in aromatic L-amino acid decarboxylase but not in tyrosine hydroxylase activity. A possible relation of this central catecholamine deficiency to the hypertension is discussed.

Effect of dietary taurine on blood pressure in spontaneously hypertensive rats.

Abstract Previous studies have shown the dietary supplementation with sulfur amino acids modified the development of hypertension in rats. In the current study, it was found that the addition of taurine (3%) to the drinking water of rats during the period of 4–14 weeks of age had little effect on blood pressure in normotensive Wistar-Kyoto rats (WKR), and slightly retarded the development of hypertension in spontaneously hypertensive rats (SHR). In the stroke-prone substrain (SHR-SP), however, there is a highly significant reduction in the development of hypertension. The endogenous content of taurine in the liver of SHR-SP is less than 50 per cent of that measured in WKR. The livers of the SHR contain an intermediate amount of taurine. The cysteic acid decarboxylase activity of liver is similar in all three strains. The tissues of animals treated chronically with taurine contain only slightly greater amounts of taurine, with small but significant increases in brain taurine being noted. It appears that genetically hypertensive rats, particularly the SHR-SP substrain, have a defect in taurine metabolism, and that this may be related to the severity of hypertension. There is no evidence to suggest that taurine plays a normal regulatory role in blood pressure maintenance.