[Does fenclonine open up new perspectives in the treatment of impotence?].
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Adult↗
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Prostaglandins: antinociceptive effect of prostaglandin E1 in the rat.
1. The antinociceptive effect of prostaglandins E1, E2 and F2alpha was studied in albino rats. Though all three prostaglandins produced similar degrees of sedation, only prostaglandin E1 (PGE1) produced a dose-related antinociceptive activity. 2. The antinociceptive activities of equi-analgesic doses of morphine (7.5. mg/kg, i.p.) and PGE1 (2.0 mg/kg, i.p.) were inhibited to almost similar extents after pretreatment with drugs known to reduce central turnover of serotonin receptors, namely reserpine, fenclonine (p-chlorophenylalanine), methysergide and 5,6-dihydroxytryptamine. 3. Prostaglandin F2alpha (2.0 mg/kg, i.p.) significantly inhibited the antinociceptive effects of both morphine and PGE1. 4. The prostaglandin synthesis inhibitors, indomethacin and diclofenac, significantly inhibited morphine analgesia. 5. Probenecid markedly prolonged the duration of antinociceptive effect of morphine and the duration of PGE1-induced potentiation of subanalgesic dose of morphine. 6. The results suggest that, in albino rats, PGE1-induced antinociceptive activity is serotonin mediated and that morphine analgesia is not only mediated through serotonin but also through prostaglandins (PGE1 ?) and 5-hydroxyindole acetic acid, the serotonin metabolite.
Analgesics↗
Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients.
Hospitalized bipolar and unipolar endogenously depressed patients who showed an antidepressant response to the monoamine oxidase (MAO) inhibitor, tranylcypromine sulfate, relapsed (ie, depression returned) when relatively small doses of parachlorophenylalanine (PCPA) were added for brief periods. Considered together with our findings that PCPA similarly reversed the antidepressant effects of the tricyclic drug, imipramine hydrochloride, implications are (1) serotonergic mechanisms are likely involved in the antidepressant effects of both the tricyclic drugs and MAO inhibitors in man and (2) this indolamine may also play a role in the endogenous clinical state of depression.
Bipolar Disorder↗
Plasma amino acids in patients with the carcinoid syndrome.
Plasma tryptophan (Trp) is reported to be decreased in some patients with the carcinoid syndrome. To determine if the plasma levels of other amino acids are also altered in the carcinoid syndrome, we used a fas-liquid chromatographic method to determine the plasma amino acid concentration of nine patients with the carcinoid syndrome and nine age-matched healthy control subjects. In comparison to the control subjects, the patients with the carcinoid syndrome had decreased plasma concentration of valine (Val), isoleucine (Ile), lysine (Lys), and ornithine (Orn), and an increased plasma concentration of methionine (Met). With the exception of a decrease in urinary excretion of proline (Pro) and hydroxyporline (Hyp), the patients with the carcinoid syndrome had normal quantities of amino acids in their urine. Plasma Met returned to normal when serotonin production by the tumor was reduced 60% by parachlorophenylalanine (PCPA); the other amino acid abnormalities persisted. Further studies are needed to determine the significance of these amino acid abnormalities.
Aged↗
Monoamines and sexual behaviour in non-human primates.
The experiments described were concerned with elucidating the involvement of monoamines in the sexual behaviour of rhesus monkeys. The measurement of perturbations in the levels and turnover of the acid metabolites of serotonin and dopamine in cisternal cerebrospinal fluid, occurring in response to hormonal manipulations which alter proceptivity and receptivity, has not clarified the ways in which hormones and amines interact. However, the use of psychoactive drugs which alter the activity of monamine neurons in the brain has demonstrated that sexual activity can be profoundly influenced by such procedures. Thus, depletion of serotonin (5-hydroxytryptamine) in the brain using p-chlorophenylalanine reversed the decrease in proceptivity that followed adrenalectomy. Conversely, inhibition of serotonin uptake using chlorimipramine reduced proceptivity and receptivity to very low levels. Both findings point to the apparently important role of serotoninergic neurons in the control of sexual behaviour. Low doses of the dopamine agonist alpha-bromocriptine enhanced the proceptivity of female rhesus monkeys but high doses had no such effect. This behavioural change was not related to the concomitant suppression of serum prolactin and may have been related to presynaptic actions of the drug in a manner postulated to explain similar behavioural effects in rats. The beta-blocker oxprenolol had the interesting property of improving the sexual performance of male rhesus monkeys, a behavioural effect consistent with an anxiolytic action, although endocrine (prolactin, cortisol) measures did not provide support for such a view. Defining the nature of the interaction between hormones and monoamine-containing neurons in the brain in behavioural contexts is shown to depend largely on the application of precise neuroanatomical and neuropharmacological techniques. However, the use of systemic treatment with psychoactive drugs used widely in clinical practice, in carefully controlled, behavioural and and endocrine experiments, is likely to provide invaluable information on where and how to investigate the neural mechanisms involved.
Adrenalectomy↗
Lipid droplet accumulation in cardiac muscle cells of the bat: potential auto-toxicity of the cardiac sympathetic innervation.
The previously described ability of reserpine and parachlorophenylalanine to induce the accumulation of lipid droplets in ventricular cardiac muscle cells of the bat was investigated. Lipid droplet accumulation was assessed qualitatively by light microscopy and quantitatively by morphometric analysis of electron micrographs. An hypothesis that the action of the drugs was an indirect one, mediated by the cardiac adrenergic innervation, was framed and tested. Lipid droplet accumulation occurred during a time of intense sympathetic activity, that of arousal from hibernation. The ability of the two drugs to produce the effect was antagonized by prior sympathetectomy with 6-hydroxy-dopamine. The effect was mimicked by administration of exogenous norepinephrine together with inhibitors of its catabolic enzymes, monoamine oxidase and catechol-o-methyl transferase. These observations are all consistent with the initial hypothesis and raise the possibility that endogenous norepinephrine in the cardiac sympathetic innervation might be, at least potentially, auto-toxic.
Animals↗
Exploration in immature rats: effects of drugs.
The effects of d-amphetamine (4 mg/kg), scopolamine (1 mg/kg), methylscopolamine (1 mg/kg), and parachlorophenylalanine (400 mg/kg) on exploration were studied in male rats at 16, 21, and 28 days of age. Amphetamine elicited stereotypy at all ages tested, reduced exploration (measured by the time spent head-dipping during a 10-min trial in a holeboard) from Day 21, but did not significantly increase rearing at the ages tested. (Reduced head-dipping, accompanied by stereotypy, is the pattern of results previously seen in adult rats with this dose of amphetamine.) An interesting difference emerged with scopolamine, which reduced head-dipping at all the ages tested, whereas in adults it produced an increase. The age-related difference in drug effects suggests that muscarinic pathways are functioning from Day 16, but that the system concerned with exploration functions differently in mature and immature rats. Both scopolamine and methylscopolamine reduced rearing which suggests that the change is due to peripheral actions of the drugs. Parachlorophenylalanine, which decreases serotonin levels, increased head-dipping, as it has been found to do in adult rats.
Aging↗
Body temperature and 5-hydroxytryptamine during early postnatal maturation in mice.
A relationship between the maturational increases in body temperature and brain indoleamines has been explored through altering brain 5-hydroxytryptamine (5-HT) content. Effects on body temperature at approximately constant ambient temperature (about 24 degrees C) have been studied following pharmacological manipulations in mice up to 16 days postpartum. Administration of 5-hydroxytryptophan (5-HTP) to increase 5-HT levels was associated with decreased body temperature throughout the maturational period. Depletion of 5-HT with p-chlorophenylalanine (p-CPA) was associated with increased body temperature at all ages studied, although 5-HT depletion was less effective in young animals than in older animals. The drug NSD-1034 acts at a different enzymatic step, and is effective in both central and peripheral tissues to reduce 5-HT and norepinephrine (NE) levels. NSD-1034 decreased body temperature up to 10 days of age; however, the effect was reversed at about 14 days, and the drug increased body temperature significantly in 16-day-old animals. These results suggest a role for 5-HT in the mechanisms of heat production in early postnatal life.
Animals↗
Phenylalanine hydroxylase in melanoma cells.
A pigmented subclone of Cloudman S91 melanoma cells, PS1-wild type, can grow in medium lacking tyrosine. This ability is conferred by phenylalanine hydroxylase activity, and not by tryptophan hydroxylase, tyrosine hydroxylase or tyrosinase activities, although the latter activity is also present in these cells. Conversion of phenylalanine to tyrosine was measured in living cells by chromatographic identification of the metabolites of [14C]phenylalanine and in cell extracts using a sensitive assay for phenylalanine hydroxylase. Phenylalanine hydroxylase activity in melanoma cell extracts was identified by its inhibition with p-chlorophenylalanine and not with 6-fluorotryptophan, 3-iodotyrosine, phenylthiourea, tyrosine or tryptophan; and by adsorption with antiserum prepared against purified rat liver phenylalanine hydroxylase, and migration of immunoprecipitable activity with authentic phenylalanine hydroxylase subunits in sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
Animals↗
Myelin deficiency in experimental phenylketonuria: contribution of the aromatic acid metabolites of phenylalanine.
Retarded body and brain growth and a deficit of myelin in the cerebral hemispheres and the cerebellum were observed in an animal model of phenylketonuria, the p-chlorophenylalanine and L-phenylalanine treated preweanling rat. These manifestations of phenylketonuria were reproduced in rats treated with phenylacetate in amounts approximating those likely to be produced in phenylketonuria. Young rats treated with equivalent amounts of other metabolites of phenylalanine, namely, phenylpyruvate, phenyllactate, and mandelate, which also accumulate in the brain during hyperphenylalaninemia, did not exhibit any toxic effects. Phenylpyruvate did not give rise to phenylacetate in the brain, but a small percentage was converted to phenyllactate. The gross composition of myelin isolated from the brains of saline and phenylacetate treated animals was similar. At various time intervals after subcutaneous injection, phenylacetate in the brain reached levels thirty times those of phenylpyruvate and phenyllactate, although animals received equivalent amounts of the three metabolites. The retarded growth of the body and brain of the young animal treated with phenylacetate may be attributed to the formation of phenylacetylcoenzyme A in the tissues. The site of action is very likely linked to acylcoenzyme A metabolism, i.e., the synthesis and utilization of acetylCoA and acetoacetylCoA, which are involved in reactions generating ATP and energy and in the synthesis of cholesterol and fatty acids. Results of this investigation indicate that growth retardation induced by phenylacetate during the period of very rapid development of the brain is responsible for the mental retardation in phenylketonuria.
Animals↗
Effect of reserpine on serum hemolysin response in mice.
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Animals↗
Respiratory depressant effects of ethanol: mediation by serotonin.
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Alcohols↗
Exocrine pancreas under experimental conditions. I. Formation of paracrystalline inclusions in vivo.
After the application of parachlorophenylalanine (pCPA), an amino acid analogue, paracrystalline inclusions are observed in the exocrine pancreas of the rat. The formation of the paracrystalline structures varies according to the dose and the time of examination. Although the first alterations can be seen in the Golgi apparatus and the condensing vacuoles, the main localization of these structures is within the cisternae of the RER. At the same time as degenerative changes occur in the cells, involving autophagic and heterophagic processes, regeneration also takes place. With the freeze-fracturing method, the paracrystalline inclusions are interpreted as lamellae or plates of probably altered secretory proteins in extremely extended RER-cisternae. The fracture surfaces of the paracrystals show a periodicity of about 80 A running diagnonally to the main axis of the paracrystalline structures, which are mainly oriented from the basal parts of the exocrine pancreatic cells to the cell apices. The mechanism of paracrystalline formation is discussed on the basis of the morphologic results. It could be shown that after pCPA administration the amylase content is decreased concomittantly with degranulation. pCPA seems not to be incorporated into secretory proteins; high intracellular concentrations, however, are required to induce the formation of the paracrystalline structures. This morphological study is the basis for other studies dealing with secretion and intracellular transport in the pancreatic acinar cell under experimental conditions.
Amylases↗
A pharmacological and autoragiographic study on the ultrastructural localization of indoleamine synthesis in the rabbit pineal gland.
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5-Hydroxytryptophan↗
Exocrine pancreas under experimental conditions. II. In vitro formation of paracrystalline structures and its functional consequences.
The in vitro formation of paracrystalline structures after addition of high concentrations of amino acids to the incubation medium was investigated in pancreatic lobules and pancreatic homogenates. It could be shown that even in the homogenate, pCPA induced the formation of paracrystalline structures which exhibited the same ultrastructural arrangement as seen in the in vivo induced paracrystalline inclusions in the RER of the rat pancreas. In correlation with the morphological alterations, the functional consequences to the secretory process, i.e. amylase discharge,discharge of pulse-labeled proteins and incorporation of 3H-leucine into pancreatic proteins,were studied in pancreaticlobules. Two different approaches were used. Firstly, the effect of pCPA-pretreatment of rats and secondly, the effect of higher pCPA concentrations in the incubation medium on the secretory process in untreated pancreatic lobules were studied. A nonparallelism of inhibition of the three different steps of the secretory process depending, with respect to its extent,on time after pCPA-application (4-72 h) and on the concentration of pCPA (1-10(-5) to 1-10(-2) M) in the incubation medium was found. In addition to specific effects probably due to pCPA and to the paracrystalline inclusions, unspecific alterations, particularly accompanying degenerative processes after in vivo pretreatment, could be differentiated.
Amylases↗
Ganglion cells and paraganglionic cells in the developing superior cervical ganglion of normal and p-chlorophenylalanine treated rats.
Ganglion cells and paraganglionic (PG) cells in the developing rat superior cervical ganglion were studied following postnatal treatment with p-chlorophenylalanine (pCPA) for 5 to 8 days. Litter mates, injected with saline solution, served as controls. Ganglion cells of control animals were differentiated ultrastructurally according to L. Eränkö (1972a) into late sympathicoblasts and young sympathetic nerve cells. In both maturation stages treatment with pCPA caused marked swelling of mitochondria, concomitant with minor changes of other cell organelles. Parallel to the ultrastructural alterations, fluorescence microscopy and cytophotometry revealed a slight diminution of diffuse fluorescence intensity in sympathetic neurons as the expression of a mainly extragranular amine depletion. In distinction from ganglion blocking agents the alterations are regarded as a general toxic effect of pCPA upon maturing sympathetic neurons, which secondarily influences catecholamine storage sites. Following treatment with pCPA, in PG-cells an alteration of mitochondria was scarcely to recognize. Specific granules were distinctly decreased in number, in some cases to an almost complete degree. Concordant to ultrastructural observations a marked diminution of fluorescence intensity was demonstrable in SIF-cells. In addition in these elements the fluorescence spectrum shifted towards the green field. Fluorescence cytophotometric evaluations confirmed the optical impression. Provided, that PG-cells, demonstrated with electron microscopy, are identical with SIF-cells in fluorescence microscopy, the results are discussed on the basis of a specific decrease of primary catecholamines due to an enzyme inhibition involved in catecholamine synthesis.
Animals↗
Light and drug induced changes of epiphysial synaptic ribbons.
In the present investigation experiments were carried out to determine whether the functionally obscure synaptic rebbons of mammalian pinealocytes can be affected by acute changes in environmental lighting and which chemical processes may be involved in their regulation. Experiments carried out in male guinea-pigs have shown that the amounts of synaptic ribbons are immediately affected by changes in the lighting pattern. Extension of the light period reduced the normally occurring increase, whereas extension of the dark period inhibited the normally occurring decrease in the amount of synaptic ribbons. Results following injections of a number of drugs known to influence pineal function (noradrenaline, L-DOPA, propranolol, reserpine and p-chlorophenylalanine, respectively) suggest that synaptic ribbons may be directly or indirectly regulated by beta-adrenergic mechanisms.
Animals↗
5-HT nerve terminals in the fourth ventricle of the rat brain: their identification and distribution studied by fluorescence histochemistry and electron microscopy.
The occurrence and distribution of supra-ependymal nerve terminals storing serotonin (5-HT) are described for the fourth ventricle of the rat brain. The nerve terminals were identified as monoaminergic 1) fluorescence-histochemically, by the presence of a varicose, formaldehyde-induced fluorescence (FIF) on the free surface of the ependyma, 2) electron microscopically, by the presence of electron dense (chromaffin) cores in small (50nm) and large (100 nm) vesicles found within the varicose regions of supra-ependymal nerve fibres, and 3) by the absence of both the FIF and chromaffin dense cores after treatment with reserpine. Moreover, the serotonergic nature of these nerve fibres could be concluded from 1) the yellow colour of the FIF, 2) the increased FIF after treatment with nialamide or reserpine+nialamide, 3) the diminished FIF and absence of chromaffin dense cores after treatment with p-CPA, and finally 4) the persistence of the FIF anc chromafin dense cores after treatment with alpha-MPT. A high density of 5-HT nerve terminals occurred throughout the floor of the fourth ventricle and on the floor and roof of the lateral recess. Few 5-HT nerve terminals occurred only on the roof of the fourth ventricle (velum medullare, lamina epithelialis of the tela chorioidea), and the surface of the choroid plexus epithelia was devoid of such nerves. Virtually all nerve terminals in the fourth ventricle appear to be serotonergic.
Animals↗