Krystyna Missala

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.

Iron- and Riboflavin-Dependent Metabolism of a Monoamine in the Rat in vivo

n-Pentylamine enters into intermediary metabolism by the action of monoamine oxidase. [1-14C] Pentylamine injected into rats is rapidly converted to 14CO2. The rate of catabolism decreases progressively in the course of nutritional iron deficiency, reaching about 60 percent of control values in 3 weeks. Feeding with iron yields control levels within 6 days. The catabolism of amyl alcohol, which shares a common pathway with n-pentylamine by way of valeric aldehyde, is not significantly affected by the deficiency. The results demonstrate that the maintenance of normal monoamine oxidase activity in vivo depends upon an adequate supply of dietary iron.

O-methylation of apomorphine and the metabolic prolongation of apomorphine-induced stereotyped behaviour

Abstract Apomorphine undergoes O-methylation in rat liver. Apocodeine, the methylated product, can be identified by paper chromatography. The catechol-O-methyltransferase inhibitors, pyrogallol and 3,4-dimethoxy-5-hydroxy-benzoic acid prolong apomorphine-induced stereotyped behaviour (ASB). This suggest that O-methylation is an important route in the biotransformation of apomorphine in vivo. Acetoaminophen also prolongs ASB; this may be related to competition for the enzymes catalyzing the glucuronidation of apomorphine.

Decrease of cerebral serotonin and 5-hydroxyindolylacetic acid caused by (—)-α-methyltryptophan1

SINCE 1956 when AMTP (a-methyltryptophan) was shown to stimulate the activity of tryptophan pyrrolase (tryptophan oxygenase; EC 1.13.1.12) in rat liver (SOURKES and TOWNSEND, 1955), this compound has been used in many biochemical experiments on the metabolism of tryptophan. The increased pyrrolase activity evoked by AMTP is analogous to that brought about by the administration of tryptophan (KNOX and MEHLER, 1950) in that it is manifested in adrenalectomized rats (CIVEN and KNOX, 1960) just as in intact animals. However, activation by tryptophan is short-lived, whereas the increased enzymic activity following a single injection of AMTP lasts for many days (SANKOFF and SOURKES, 1962). Chronic elevation of hepatic pyrrolase could lead to a relative deficiency of the indispensable amino acid tryptophan (MADRAS and SOURKES, 1965), and this could affect the formation of important compounds derived from it, namely, tryptamine, serotonin, melatonin and NAD, as well as many proteins. In this paper the effect of AMTP on the concentration of serotonin and its acid metabolite 5H I M (5-hydroxyindolylacetic acid) in the brain is assessed. The availability of the separate isomers of AMTP enabled us to determine the contribution of each to this effect, as well as to other actions of AMTP.

Alpha-methyltryptophan: Effects on synthesis and degradation of serotonin in the brain ☆

Abstract Alpha-methyltryptamine and α-methylserotonin have been detected in the brain following the administration of doses of AMTP (α-methyltryptophan) of 50 mg/kg or greater. At 4–6 hr after a single injection of AMTP the concentration of α-methyltryptamine was very much smaller than that of α-methylserotonin. The concentration of the latter substance was followed as a function of time after the administration of AMTP. There was a gradual increase of α-methylserotonin and decrease of serotonin so that the concentration of α-methyl-serotonin rose to 6 times that of the naturally occurring amine in 48 hr, falling to 3 times its concentration in 96 hr. Control levels of 5-hydroxyindoleacetic acid and of material measured fluorometrically as serotonin were eventually attained 8–10 days after the injection of AMTP. The influence of AMTP on the concentrations of brain 5-hydroxyindoleacetic acid and serotonin-like substances (i.e. serotonin and α-methylserotonin) was studied in relation to the actions of various drugs. Treatment of rats with sufficient p-chlorophenylalanine to lower the concentration of serotonin and 5-hydroxyindoleacetic acid in the brain by 50% did not prevent the appearance of substantial amounts of α-methylserotonin in the brains of AMTP-treated animals. On the other hand, the decarboxylase inhibitors Ro4-4602 and NSD-1055, both prevented formation of α-methylserotonin from AMTP. Reserpine, 2 monoamine oxidase inhibitors, and probenecid were also tested for interaction with AMTP. The results with respect to cerebral 5-hydroxyindoleacetic acid were generally interpretable on the basis of independent actions of the drugs.

Putrescine catabolism in rats given heparin or aminoguanidine.

Rats treated acutely with aminoguanidine, a potent inhibitor of diamine oxidase, or with heparin display reduced ability to metabolize 14C-putrescine to radioactive carbon dioxide. After either drug rats recover 50% of the ability to catabolize putrescine in 15--18 h. This is in close agreement with the half-time for recovery of diamine exidase activity, and indicates that putrecine-catabolizing ability of the rat reflects in a physiologically significant way the function of diamine oxidase in vivo.

Conversion of 14C-dopamine to cardiac 14C-noradrenaline in the copper-deficient rat☆

Abstract Rats that were fed a diet deficient in copper for 7–13 weeks showed a greatly decreased rate of conversion of parenterally administered 14 C-dopamine (dihydroxyphenylethylamine) to cardiac 14 C-noradrenaline as compared with control animals. This reduced activity of dopamine-β-hydroxylase in vivo was associated with a decline in the concentration of copper in heart and liver. Provision of a supplement of cupric sulphate to rats fed the copper-deficient diet for 12 weeks restored to normal the rate of formation of labelled noradrenaline as well as the tissue concentration of copper. Young rats (45–55 g) carry out the conversion of exogenous dopamine to cardiac noradrenaline faster than adult rats. There were no differences in these experiments between albino and hooded (black and white) rats.

Effect of neuroleptics on brain amphetamine concentrations in the rat

Within certain dose ranges promazine, chlorprothixene (Halliwell, Quintin & William, 1964) and triflupromazine prolong amphetamine-induced stereotyped behaviour (ASB). We now report the effect of these four neuroleptics on brain amphetamine concentration. Male Sprague-Dawley rats, about 150 g, were housed in pairs in wire cages, and groups of six injected with either triflupromazine hydrochloride (Vesperin, Squibb), promazine hydrochloride (Sparine, Wyeth), chlorprothixene (Tarasan, Roche), each in a dose of 5 mg/kg, perphenazine (Trilafon, Schering), 1 mg/kg, or distilled water 2 h before (+)-amphetamine sulphate (Smith, Kline and French), 10 mg/kg containing 66 pCi/kg [3H]amphetamine (New England Nuclear). Two animals in each group were killed at 30, 120 and 240 min and amphetamine concentrations measured in the brain. The procedure for extraction and measurement of [3H]amphetamine was that of Lemberger, Witt & others (1970). For behavioural effects, animals received similar treatment except that radioactive amphetamine was not added to the cold amphetamine. The duration of ASB was recorded by direct observation. Additional control rats received either distilled water or neuroleptic but no amphetamine. The pH of urine was found to range from

Central Regulation of Adrenal Tyrosine Hydroxylase: Effect of Induction on Catecholamine Levels in the Adrenal Medulla and Plasma

Abstract: The effect of induction of adrenal tyrosine hydroxylase (TH) by various centrally acting drugs on catecholamine levels in adrenal and plasma was investigated in rats. All the drugs tested, namely oxotremorine, Piribedil, B‐HT 920, and HA‐966, produced significant increases in adrenal dopamine content and plasma epinephrine level. Denervation of the adrenal abolished the increase in adrenal dopamine as it did the induction of tyrosine hydroxylase. The results suggest that the induced increase of adrenal TH activity, as mediated by certain drugs, results in an elevation of the plasma epinephrine level and that the adrenal dopamine content is a better indicator of the catecholamine‐synthesizing capacity of the adrenal medulla than are the other catecholamines.

Alpha-methylserotonin, a substitute transmitter for serotonergic neurons

1. Administration to rats of alpha-methyltryptophan (AMTP) gives rise to alpha-(AM5HT) in the brain along with a decrease of cerebral 5HT. 2. Analysis of fractions prepared from brains of AMTP-injected rats shows that AM5HT occurs mainly in the synaptosomes. 3. The synaptosomal content of AM5HT in proportion to the total AM5HT in the brain represents the same ratio as for the corresponding fractions of 5HT.