Theodore L. Sourkes

Monoamine metabolites in lumbar CSF: The question of their origin in relation to clinical studies

Abstract The sources of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and 5-hydroxyindoleacetic acid (5HIAA) in lumbar CSF of man are discussed. Although HVA in lumbar CSF is derived from the brain, and MHPG seems to be mainly from the spinal cord, the origin of 5HIAA is uncertain. The evidence for and against a brain contribution to 5HIAA of the lumbar CSF is evaluated. It is concluded that the brain can contribute 5HIAA to lumbar CSF under some circumstances. Measurement of 5HIAA concentrations in lumbar CSF can be of clinical value in detecting changes of 5-hydroxytryptamine (5HT) metabolism in the CNS if the changes are general throughout the CNS.

Excretion of Dopamine in Diseases of Basal Ganglia

The urinary excretion of catecholamines has been measured in 32 patients with disorders of the basal ganglia. Sixteen patients with Parkinsonism (idiopathic, postencephalitic, and arteriosclerotic types) had a significantly lower amount of dopamine in the urine during a 24-hour period than a group of 24 normal control subjects. In a group of 16 patients with various striatal syndromes the excretion of dopamine and epinephrine was significantly higher than normal. Norepinephrine excretion was similar in the three groups. The lowest mean value of urinary dopamine was found in postencephalitic Parkinsonism; the highest occurred in Wilsons disease.

Serotonin synthesis rate measured in living dog brain by positron emission tomography

Abstract: In vivo measurements by positron emission tomography of the brain serotonin synthesis rates in the normal dog, in the dog with increased plasma tryptophan concentration, and in the dog under different arterial oxygen tensions are described. The method described here permits repeated measurements in the same brain for the first time. An increase in the plasma tryptophan concentration from 16.6 to 191.5 and then to 381 μM resulted in close to a linear increase in the brain serotonin synthesis rate. When PaO2 was raised from 76 ± 2 to 106 ± 1 mm Hg, the rate of serotonin synthesis in the dog brain increased from 39 ± 8 to 54 ± 10 pmol g−1 min−1. The estimates of the Michaelis‐Menten constants, Kappm and Vmax for the transport of tryptophan through the blood‐brain barrier are 303 ± 54 μM and 63 ± 10 nmol g−1, min−1, respectively.

Transport of L-tryptophan into slices of rat cerebral cortex.

—Slices of rat cerebral cortex, when incubated aerobically at 37°C in Krebs‐Ringer‐phosphate solution (pH 7.0) containing 10 mm glucose and 1.0 mm l‐tryptophan [1‐14C], accumulated tryptophan. Within the first 15 min of incubation the ratio of the concentration of the amino acid in the tissue to that in the medium reached 3.5:1. Uptake of tryptophan was linear for the first 30 min and attained a maximum concentration ratio (tissue:medium) of 6.5:1 within 60 min. The transport mechanism became saturated at 1.0‐3.0 mm tryptophan. Entry of the amino acid into the cortical cells was thereafter directly proportional to its initial concentration in the medium.

The effect of yohimbine on brain serotonin metabolism, motor behavior and body temperature of the rat

Abstract Yohimbine, 5 or 20 mg/kg given intraperitoneally, increased the concentration of brain serotonin and decreased that of 5-HIAA, in the rat. The changes occurred in 2–4 hr after administration of the alkaloid. Changes in the same direction as brain were observed for serotonin in the intestine. Tryptophan in the blood was slightly increased at 2 hr, but no change was detected in the brain. MAO activity in vitro was inhibited only by the higher concentration of yohimbine; no inhibition was observed in vivo in the brain and the liver. Yohimbine induced also a dose-dependent decrease of spontaneous locomotion and of body temperature. Corynanthine, an isomer of yohimbine, did not cause any of the above changes at the same dose levels. The results are discussed in terms of inhibition of tryptophan pyrrolase by yohimbine as well as the possible stimulation of serotonin receptors by yohimbine. This drug could be considered as a potential tool to test the involvement of serotoninergic processes in endogenous depression.

SOME ENZYMIC ASPECTS OF THE PRODUCTION OF OXIDIZED OR REDUCED METABOLITES OF CATECHOLAMINES AND 5‐HYDROXYTRYPTAMINE BY BRAIN TISSUES

The Michaelis constants of purified aldehyde dehydrogenase (aldehyde: NAD oxidoreductase, EC 1.2.1.3) and aldehyde reductases (alcohol: NADP oxidoreductase, EC 1.1.1.2) from pig brain have been obtained for a number of biologically important aldehydes. The aldehydes include 3,4‐dihydroxyphenylacetaldehyde, D‐3,4‐dihydroxyphenylglycolaldehyde, and 5‐hydroxyindoleacetaldehyde. The relative activities of the aldehyde‐catabolizing enzymes in the soluble fractions of the cerebral cortex and caudate nucleus of pig brain have also been obtained. The values are used to show that the metabolic fates of the various aldehydes—and hence of the parent amines—may be explained in terms of the simple kinetics of these enzymes. It is also shown that the metabolic fates of the aldehydes may be influenced by their rates of synthesis. As the rate of aldehyde production increases the proportion of aldehyde reduced may be expected to increase at the expense of the proportion of aldehyde oxidized.

Effect of amine precursors on the concentration of striatal dopamine and serotonin in cats with and without unilateral brain stem lesions

Abstract A study of the effect of amine precursors on the concentration of dopamine and serotonin in the striata of the brains of normal cats and of cats with unilateral brain stem lesions gave the following results. The i.p. injection of dl -DOPA and of dl -5-HTP into normal cats produced a marked increase of the striatal dopamine and serotonin, respectively. The i.p. injection of dl -DOPA into cats with unilateral brain stem lesions that completely severed the nigro-striatal pathways and did not influence the depletion of dopamine in the corresponding striatum but produced a marked increase of dopamine in the striatum of the intact side. Such lesions were associated with a complete disappearance of the neurons (retrograde degeneration) in the ipsilateral substantia nigra and nucleus parabrachialis pigmentosus which are responsible for the elaboration of dopamine. The i.p. injection of dl -5-HTP into cats with unilateral brain stem lesion that interrupted the striatopetal fibers responsible for regulating the serotonin content of the striatum did not modify the complete, or nearly complete, depletion of serotonin in the corresponding striatum although it markedly increased the concentration of serotonin in the striatum of the intact side of the brain. Such lesions are associated with a retrograde cellular degeneration in some basomedial cell groups of the upper pons and lower midbrain on the side of the lesion. Consequently, the use of dopamine and serotonin precursors to compensate for a loss of those biogenic amines from the striatum as encountered in some extrapyramidal syndromes could be of value only where some functioning striatopetal neurons persist.

THE ACTION OF SOME α-METHYL AND OTHER AMINO ACIDS ON CEREBRAL CATECHOLAMINES*

IT HAS been shown recently that AMDPt, a t first studied as an inhibitor of mammalian DOPA? decarboxylase in z’itro and of the tyrosine decarboxylase of Str. fiecalis R (SOURKES, 1954), acts in vico upon the decarboxylation of DOPA (DENGLER and REICHEL, 1958 ; MURPHY and SOURKES, 1959), 5-hydroxytryptophan (WESTERMANN, BALZER and KNELL, 1958; SMITH, 1960; OATES, GILLESPIE, UDENFRIEND a,nd SJOERDSMA, 1960), tyrosine and tryptophan (OATES et a/., 1960). This action on the decarboxylation of DOPA in riro is also displayed by a-methyl-3-hydroxyphenylalanine (a-methyl-m-tyrosine) (SOURKES, MURPHY and WOODFORD, 1960) as well as by amethyl-2-hydroxyphenylalanine (a-methyl-0-tyrosine), a-methyl-2:5-DOPA, and amethyl-5-hydroxytryptophan (MURPHY and SOURKES, 1961). By use of fluorometric methods it has been shown (MURPHY and SOURKES, 1959) that AMDP administered parenterally to the rat has two effects upon the cerebral catecholamines: one of decreasing the concentration of the endogenous amines and, secondly, of interfering with the conversion of exogenous DOPA to cerebral dopamine and noradrenaline. Although the injected AMDP is found in the brain in concentrations known to be effective for the inhibition of DOPA decarboxylase the rapid decrease in cerebral catecholamines could conceivably be due to some other mechanism than through inhibition of the decarboxylation. In this paper the amine-depleting action of AMDP has been further studied. Moreover, some other amino acids have been tested to compare their ability with that of AMDP in depleting the brain of its catecholamines.

Effects of aporphine and emetine alkaloids on central dopaminergic mechanisms in rats.

Abstract A series of aporphine and emetine alkaloids was studied for induction of stereotyped behaviour (SB), antagonism of reserpine sedation, and effect on the cerebral concentrations of homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in the rat. Apomorphine (5 mg/kg) induced SB, reversed the reserpine syndrome and lowered the concentration of cerebral HVA. Apocodeine (10-O-methylapomorphine) and methylenedioxyaporphine (both injected in a dose of 20 mg/kg) induced intermittent SB, reversed the reserpine syndrome and reduced cerebral HVA, whereas 10,11-dimethoxyaporphine had none of these effects. Methylenedioxyaporphine decreased the level of 5-HIAA slightly. The results suggest that apocodeine and methylenedioxyaporphine have similar sites of action to those affected by apomorphine, but that the first 2 alkaloids are less potent agonists than apomorphine. 6 other analogues of apomorphine, including 1,2,10,11-tetrahydroxyaporphine (the N-methyl derivative of a compound theoretically derivable from tetrahydropapaveroline), were tested at doses of 20 mg/kg, but none induced SB. Cephaeline and emetine did not influence the concentrations of HVA or 5-HIAA in the brain, nor did they induce SB.

Central dopaminergic and serotoninergic systems in the regulation of adrenal tyrosine hydroxylase.

Administration of the dopamine receptor agonists apomorphine, piribedil and bromocryptine caused an increase in adrenal tyrosine hydroxylase (TH; tyrosine‐3‐monooxygenase, EC 1.14.16.2) which could be partially abolished by prior injection of the dopamine blocker haloperidol. Injection of L‐dihydroxyphenylalanine, along with the decarboxylase inhibitor carbidopa, also led to a highly significant increase in adrenal TH activity. Intraventricular injection of 5,7‐dihydroxytryptamine (DHT), which destroys serotonin neurons, doubled adrenal TH activity in both normal and hypophysectomized rats. Splanchnicotomy abolished this effect of DHT. The increase in enzyme activity mediated by DHT could be partially prevented by peripheral administration of L‐5‐hydroxytryptophan together with carbidopa. Blockade of serotoninergic functions with the antagonist methiothepin also increased adrenal TH activity. The interrelationship between the dopamine and the presumed serotonin system was investigated. Intraventricular injection of 6‐hydroxydopamine partially prevented the DHT‐induced increase in adrenal TH activity. Administration of haloperidol to DHT‐treated rats had the same effect. This suggests that an intact dopaminergic system is required. When DHT and either apomorphine or piribedil were adminstered simultancously the dopamine agonist‐induced increase was potentiated. An intact serotoninergic system is therefore not required for dopamine function.