The presence of 2'', 3''-cyclic AMP 3''-phosphohydrolase in glial cells in tissue culture

Abstract— T he E nzyme 2', 3'-cyclic AMP 3'-phosphohydrolase (CNP) is regarded as a marker for myelin (KURI- HARA and MANDEL, 1970) on the basis of its regional and subcellular distribution (K urihara and T sukada , 1967), its ontogenetic characteristics (KURIHARA and TSUKADA, 1968), and its behaviour in two strains of myelin-deficient mutant mice (K urihara , N ussbaum and M andel , 1969). However we have isolated highly-purified preparations of neuronal plasma membrane from rat brain synaptosomes which contain this enzyme activity (M organ , W olfe , M andel and G ombos , 1971). Two explanations of this finding are possible. The activity could be due to the presence of myelin, but this explanation is ruled out by electron microscopy and by the low level of cerebrosides in the synaptosomal plasma membrane preparations. Myelin is extremely rich in cerebrosides ( norton and A utilio , 1966). The second possibility is that the enzyme, 2', 3'-cyclic AMP 3'-phosphohyrolase, may also be found in the glial cells from which myelin is derived (B unge , B unge and P appas , 1962). To test our hypothesis that 2', 3'-cyclic AMP 3'-phosphohydrolase is not a specific marker for myelin, but is also found, in glial cells, we have examined a tumoral glial cell line maintained in myelin-free tissue culture.     

Tyrosine hydroxylase activity in rat brain following "REM" sleep deprivation

I n R ecent years biogenic amines have been implicated in the control mechanism for induction and maintenance of sleep processes (J ouvet , 1969). Investigators have looked for changes in the rate of synthesis of cerebral norepinephrine from [³H]tyrosine after REM sleep deprivation and reported increased rates of synthesis during REM sleep deprivation (M ark , H einer , M andel and G odin , 1969) and REM sleep rebound following 91 h of deprivation (P ujol , M ouret and G lowinski , 1968). Because tyrosine is thought to be the rate-limiting enzyme (U denfriend , 1966) in the synthetic pathways for norepinephrine and since the above-mentioned studies are suggestive of changes in the activity of the enzyme, we decided to measure tyrosine hydroxylase activity following REM sleep deprivation.     

Monoamine Changes in the Brain of BALB/c Mice Following Sub-Lethal Infection with Nocardia asteroides (GUH-2)

BALB/c mice injected intravenously with a single, sub-lethal dose of Nocardia asteroides GUH-2 develop several levodopa responsive movement disorders. These included head-shake, stooped posture, bradykinesia, and hesitation to forward movement (6). The changes in monoamine levels in the brain of these mice were determined. There was a significant loss of dopamine with greatly increased dopamine turnover in the neostriatum 7 to 29 days after infection. These effects were specific for dopaminergic neurons since minimal changes were found in neostriatal norepinephrine and serotonin even though serotonin turnover was increased. Changes in monoamine metabolism were not limited to the neostriatum. There were reduced levels of serotonin and norepinephrine with increased serotonin turnover in the cerebellum. One year after infection, dopamine metabolism had returned to near normal levels, but many of the movement disorders persisted. Specific changes in neurochemistry did not always appear to correspond with these impairments. Nevertheless, these data are similar to those reported in MPTP treated BALB/c mice.     

Identification of serotonin-modulated protein fraction and study of its role in passive avoidance reaction in rats]

The effect 10(-3) M serotonin and norepinephrine solutions application on the brain occipital cortex on discrete water soluble protein fractions content was investigated in narcotized rats. It was revealed that application of serotonin solution caused repeated decrease in N6 fraction content. Immunoglobulins against N6 fraction being injected into the lateral ventricle of rat brain increased the number of photocell crossing and the presence probability of rats at the dark compartment entrance region in passive avoidance schedule. The conclusion of selective serotonin participation in regulation of brain cortex discrete proteins turnover and of these proteins involvement in searching behavior was made.     

Serotonin and norepinephrine

Rats which had been primed with the serotonin depletor,p-chlorophenylalanine, and sacrificed months later were found to have the same resting levels of brain serotonin and norepinephrine as unprimed controls. However, when treated with the monoamine oxidase inhibitor, tranylcypromine, the former showed a significantly lower accumulation of these biogenic amines than their tranylcyprominetreated unprimed counterparts. These findings indicate that brain serotonin, which had been lowered at the outset byp-chlorophenylalanine, had returned to normal levels but that the priming procedure might have resulted in a long-term decrease in the turnover rates of serotonin as well as norepinephrine. Primed animals may prove suitable as models of disturbed biogenic amine metabolism with possible relevance to schizophrenia and other brain dysfunctions.     

Besprechungen

Book reviewed in this article: Alexander , B. K., und E. M. Roth (1971): The effects of acute crowding on aggressive behavior of Japanese Monkeys Brown , Jerram L. (1971): An exploratory study of vocalization areas in the brain of the Red winged Blackbird Hogan , Jerry A. (1971): The development of a hunger system in young chicks Castell , Rolf, und Carolyn Wilson (1971): Influence of spatial environment on development of mother-infant interaction in Pigtail Monkeys Yadava , R. P. S., und M. V. Smith (1971): Aggressive behaviour of Apis mellifera L. workers towards introduced queens Kovach , Joseph K. (1971): Ethology in the Soviet Union Wiepkema , P. R. (1971): Positive feedbacks at work during feeding Hafez , Mahmud, H. S. Salama und R. A. Tolba (1971): Reactions of the corn borer Schmidt , Robert S. (1971): A model of the central mechanisms of male Anuran acoustic behavior Davenport , R. K. und G. M. Rogers (1971): Perception of fotografs by apes ed. Carthy , J. D., und G. E. Newell (1968): Invertebrate receptors Rensch , Bernhard (1971): Probleme der Gedächtnisspuren Tinbergen , N. (1971): Clever gulls and dumb ethologists — or: the trackers tracked De Lannoy , J., und M. Wielerrians (1969): Le schéma du jeune congénère Gray , Annie P. (1971): Mammalian hybrids, a check-list with bibliography     

Influence of dieldrin on serotonin turnover and 5-hydroxyindole acetic acid efflux in mouse brain

Chronic administration of dieldrin failed to produce any alteration of brain serotonin, norepinephrine or dopamine in mice, but caused an increase in 5-hydroxyindole acetic acid levels. The turnover rate of serotonin was unaffected by dieldrin. The probenecid induced accumulation rate of 5-hydroxyindole acetic acid was considerably lowered in dieldrin-treated mice. The results suggested a possible influence of dieldrin on 5-hydroxyindole acetic acid efflux from mouse brain.     

Accumulation of adenosine 3'',5''-monophosphate in incubated slices from discrete regions of squirrel monkey cerebral cortex: effect of norepinephrine, serotonin and adenosine

THE ROLE of adenosine 3′5′-monophosphate (cyclic AMP) in the central nervous system is as yet unknown. However, a variety of putative neurotransmitters such as norepinephrine, serotonin and histamine have been found to elicit enhanced accumulations of cyclic AMP in cerebral cortical slices from a variety of species (SHIMIZU and DALY, 1972; FORN and KRISHNA, 1971; SHIMIZU, TANAKA, SUZUKI and MATSUKADO, 1971; FUMAGALLI, BERNAREGGI, BERTI and TRABUCCHI, 1971). In addition, depolarization of membranes in cortical slices elicits a marked accumulation of cyclic AMP, probably mediated through the action of adenosine (KAKIUCHI, RALL and MCILWAIN, 1969; SHIMIZU. CREVELING and DALY, 1970). These results, obtained with grey matter from the entire cerebral cortex, suggest an intimate relationship between neuronal activity, release of putative neurotransmitters, and enhanced accumulation of cyclic AMP in brain tissue. Since innervation and electrical activity in the cerebral cortex differs among functionally distinct neocortical areas and in the histologically distinct limbic cortex, it appeared possible that these differences would also be manifest in the regional control of cyclic AMP levels. We now report that the response of the cyclic AMP generating system to putative neurotransmitters and adenosine does differ among discrete functional regions of the squirrel monkey cerebral cortex.     

Increase of brain tryptophan and stimulation of serotonin synthesis by salicylate

I ndirect evidence indicates that the rate-limiting step in the synthesis of brain 5-HT is the concentration of tryptophan in brain and not, as previously considered (G reen and S awyer , 1966), tryptophan hydroxylase. In fact this enzyme has a K_m for its substrate much higher than the concentration of tryptophan normally present in the mammalian brain (J equier , L ovenberg and S joerdsma , 1967; J equier , R obinson , L ovesberg and S joerdsma , 1969; M cgeer , P eters and M cgeer , 1968). Tryptophan is the only amino acid circulating in plasma which is highly bound to serum proteins (M cmenamy and O ncley , 1958). We have previously shown that the free fraction of serum tryptophan controls the concentration of brain tryptophan and, therefore, 5-HT synthesis as well (T agliamonte , B iggio and G essa , 1971d; G essa , B iggio and T agliamonte , 1972). Salicylate has been shown to displace tryptophan from its protein binding in plasma and to raise the free tryptophan concentration (M carthur and D awkins , 1969; S mith and L akatos , 1971). These considerations prompted us to study the effect of salicylate on tryptophan concentrations and 5-HT metabolism in brain.     

The Effects of Cholinergic and Dopaminergic Antagonists on Nicotine-Induced Cerebral Neurotransmitter Changes

In a continuing study of nicotine-induced mechanisms in brain areas associated with cognitive processes, the effects of cholinergic and dopaminergic antagonists on nicotine-induced changes in dopamine, norepinephrine, and serotonin were examined. These effects were measured via in vivo microdialysis in the dorsal and ventral hippocampus and in the prefrontal and medial temporal cortex of conscious, freely moving, adult male rats. Nicotine (0.3 mg/kg, free base) was administered subcutaneously and the antagonists were infused locally via the microdialysis probe. Nicotine alone induced an increase of dopamine and its metabolites in all areas, an increase of norepinephrine in the cortex, and an increase of the norepinephrine metabolite 4–hydroxy-3-methoxy-phenylglycol in all areas. Serotonin was decreased in the hippocampus and increased in the cortex. Nicotine-induced dopamine increases were inhibited by nicotinic (mecamylamine 100 μM, methyllycaconitine 500 μM), muscarinic (atropine 100 μM), and dopaminergic D1 (SCH23390 100 μM) and D2 (eticlopride 100 μM) antagonists, in the hippocampal and cortical areas. In the hippocampal areas, these antagonists had less significant effect on norepinephrine and serotonin. However, in the cortical areas, all antagonists inhibited the nicotine-induced increase of serotonin to varying degrees; and some, primarily nicotinic and dopamine D1 antagonists, inhibited the induced increase of norepinephrine. In the hippocampal and cortical areas, the mechanisms of nicotine-induced dopamine increase seem to be similar, but the mechanisms seem to be different for noradrenergic and serotonergic systems, as shown by the fact that nicotine induces no change in norepinephrine and a decrease in serotonin in the hippocampus, while it induces an increase in both in the cortex. Nicotine-induced dopamine release seems to be mediated, in part locally, by nicotinic and muscarinic receptors on dopaminergic cells. In contrast, nicotine’s effect on norepinephrine and serotonin is at least partially mediated by initial changes at other than local sites, and through different receptors. Thus, the effects of nicotine and the mechanisms involved differ for different neurotransmitters and in different brain areas.     

Book Reviews

Book Review in this Article
A erobiology : P roceedings of the T hird I nternational S ymposium , 1970. Edited by I. H. Silver
M odern F ood M icrobiology , 1971. James M. Jay.
W ater T reatment and E xamination , 1970. Edited by W. S. Holden.
M icrobial A spects of M etallurgy , 1971. J. D. A. Miller.     

Changes in the pituitary metabolism of monoamines (dopamine, norepinephrine, and serotonin) in female and male rainbow trout (Oncorhynchus mykiss) during gonadal recrudescence

The dynamics of the levels and metabolism of dopamine, norepinephrine, and serotonin were studied in pituitaries of male and female rainbow trout at different stages of gonadal development. In female rainbow trout, the turnover of dopamine (calculated using the inhibitor of tyrosine hydroxylase alpha-methyl-p-tyrosine methyl-ester HCl), serotonin metabolism, and norepinephrine levels decreased in the advanced stage of exogenous vitellogenesis with respect to the initial stage. However, data obtained in males did not show changes in either serotonergic or noradrenergic metabolism during the last stages of gonadal development. However, an increase of dopaminergic turnover was noticed in the male fish at the end of spermiation. Finally, pituitary dopaminergic activity was significantly higher in immature (prepubescent stage) than in adult fish.     

Brain serotonin and norepinephrine after convulsions and reserpine

Decreased brain norepinephrine (Schildkraut , 1969) and decreased brain serotonin (Shaw , Camp and Eccleston , 1967; Bourne et al., 1968) have been implicated in current hypotheses about the psychiatric syndrome, depression. Reserpine, which causes depression in some people, depletes brain norepinephrine and serotonin and, possibly, replicates in laboratory animals some of the biochemical changes in brains of depressed patients. Electrically-induced convulsions are an effective treatment of depression. There have been numerous studies of the effects of convulsive electrical stimulation on norepinephrine and serotonin in brains of laboratory animals. They have employed different schedules of administration of convulsions, short (minutes) or long (hours to days) periods after convulsion before killing the animals, and various methods of extraction and assay of the amines. Results have varied. For example, Kato , Gozsy , Roy and Groh (1967) found that a series of convulsions, administered daily for 11 days elevated whole brain serotonin but not norepinephrine. On the other hand, Hinesley , Norton and Aprison (1968) observed that a series of seven convulsions, one every other day, elevated norepinephrine only in cerebral hemispheres, whereas serotonin was elevated only in midbrain and pons-medulla. Our present report is the first to deal with both norepinephrine and serotonin in animals given both serial injections of reserpine and a series of electrically-induced convulsions.     

Isolation of glycosaminoglycans and variation with age in the feline brain

M any laboratories have reported the presence of glycosaminoglycans (GAG) in the brains of a variety of species, including monkey, man, cat, pig, rabbit, sheep, rat and chicken (C handrasekaran and B achhawat , 1969; C lausen and H ansen , 1963; C lausen and R osenkast , 1962; C ustod and Y oung , 1968; M argolis , 1967; O nodera , H irona , H oriuchi and K ashimura , 1966; S aigo and E gami , 1970; S ingh and B achhawat , 1965 , 1968; S ingh , C handrasekaran , C herian and B achhawat , 1969). Because of the interest of our laboratory in the GAG of the cat brain (C ustod and Y oung , 1968; Y oung , 1963), we initiated the present studies to quantify these various brain polysaccharides and to investigate their changes as a function of postnatal age.     

Involvement of brain stem noradrenergic neurons in the development of hypertension in spontaneously hypertensive rats

This study attempted to investigate the possible involvement of the brain stem noradrenergic system in the development of hypertension in spontaneously hypertensive rats. Steady-state norepinephrine, dopamine, serotonin and 5-hydroxyindoleacetic acid concentrations and norepinephrine turnover were determined in the individual brain stem nuclei using high performance liquid chromatography with electrochemical detection. Decreased norepinephrine contents in the nucleus tractus solitarii in spontaneously hypertensive rats compared with Wistar-Kyoto rats at the age of 4, 8, and 16 weeks were demonstrated. In later stages (8 and 16 weeks), increased norepinephrine levels were observed in the nucleus reticularis gigantocellularis, the A1 and A5 areas. Norepinephrine turnover was not different between spontaneously hypertensive rats and Wistar-Kyoto rats in the nucleus tractus solitarii at the age of 4 and 16 weeks and increased in the nucleus reticularis gigantocellularis of spontaneously hypertensive rats at 16 weeks. Our results indicate that altered norepinephrine metabolism in the specific brain stem nuclei, especially the consistently decreased norepinephrine in the nucleus tractus solitarii of spontaneously hypertensive rats, contribute to the development of genetic hypertension.     

Male and female mice living in differently-sized groups

Summary The influence of crowding in different group sizes on the metabolism of serotonin (5-HT) in six different brain areas and on some peripheral data in male and female mice was investigated. In the cortex, the diencephalon and in the basal ganglia, the 5-HT turnover of male mice increases with group size. The females react differently (Figs. 2, 3, 4). The densityinduced changes in the 5-HT metabolism of the mesencephalon correlated individually with the locomotor reactivity of the animals in an open-field (Figs. 8, 9). The septal area is the only part of the brain in male and female mice in which the 5-HT turnover increase depends on group size (Fig. 5).We wish to thank the Deutsche Abbott GmbH which supplied us with pargyline.     

CADMIUM ALTERS BEHAVIOUR AND THE BIOSYNTHETIC CAPACITY FOR CATECHOLAMINES AND SEROTONIN IN NEONATAL RAT BRAIN1

Abstract— Daily exposure to cadmium (10 μg/100g) for 30 days since birth significantly increased spontaneous locomotor activity as well as striatal tyrosine hydroxylase and mid-brain tryptophan hydroxylase. The endogenous levels of norepinephrine, dopamine and serotonin failed to change in various brain regions of cadmium-treated rats. In contrast, the concentration of 5-hydroxyindoleacetic acid tended to rise but was significantly different from controls only in the mid-brain region. The data suggest that cadmium treatment in early life increased the synthesis and physiological utilization of these putative transmitters which in turn probably altered locomotor performance. Increasing the dose of cadmium to 100 μg/100 g for 30 days decreased body weight (by 19%) and produced slight increases in the turnover of brain amines. However, the rise was not dose-dependent. Furthermore, the locomotor activity remained the same as that seen in rats treated with the low dose of cadmium. The levels of dopamine in hypothalamus and that of norepinephrine in several brain regions examined were enhanced. This could in part, be attributed to decreased (12%) activity of catechol-O-methyl transferase enzyme. Administration of the high dose of cadmium produced significant increases in 5-hydroxyindoleacetic acid level. Data suggest that cadmium acts at some step in the sequence of intracellular events that leads to increased synthesis and presumably turnover of brain catecholamines and serotonin. Since high dosage of this heavy metal failed to produce a dose-dependent change in locomotor activity, it is not possible to impute any casual role for these amines in the production of hyperactivity seen in cadmium-treated rats.     

The relative constancy of the glycogen content of guinea pig brain

U sing mice and rats as experimental animals, a variety of treatments have been reported which bring about a marked increase in the glycogen content of the brain. These treatments have included injections of phenobarbitone (N elson , S chulz , P assonneau and L owry , 1968), methionine sulphoxime (F olbergrová , P assonneau , L owry and S chulz , 1969), lithium (R afaelson , P lenge and M ellerup , 1969) and a glucocorticoid (T imiras , W oodbury and B aker , 1956), and also manipulation of the blood sugar level with and without concomitant administration of insulin (N elson et al. , 1968; P rasannan , R ajan and S ubraharyam , 1963; P rasannan and S ubrahmanyam , 1965). The present communication is concerned with the response of the guinea pig to these treatments and demonstrates that, in this animal, they are either totally without effect or are less effective than in mice and rats.     

Consequences of renal mass reduction on amino acid and biogenic amine levels in nephrectomized mice

Summary. Amino acid and biogenic amine changes were investigated in nephrectomized mice ten days postsurgery. Uremic mice exhibited changes in amino acid concentrations in plasma, urine and brain. Particularly plasma methionine, citrulline and arginine levels were significantly enhanced in nephrectomized mice compared to controls whereas serine was decreased. Urinary excretion of methionine, citrulline and alanine was higher in nephrectomized mice compared to controls whereas many amino acids were increased in brain of nephrectomized mice. Brain and urinary amino acid changes were more pronounced in the 75% than in the 50% nephrectomized mice. Brain norepinephrine and dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were significantly increased whereas serotonin was decreased comparing the 75% nephrectomized mice to the sham-operated mice. This study demonstrates that at very early stages of renal insufficiency, specific amino acid and biogenic amine changes occur in plasma, urine and brain. These alterations might depend qualitatively and quantitatively on the degree of functional renal mass reduction. Received April 5, 1999     

Increased monoamine oxidase activity following repeated electroshock seizures

W e H ave recently reported that chronic electroconvulsive seizures (ECS) lead to a long-lasting increase (up to 6 weeks) in the activity of monoamine oxidase (MAO) in the brain of rats (P ryor and O tis , 1970). Other investigators have shown increased levels of norepinephrine (NE) and 5-HT, more rapid clearance of intracisternally-injected [³H]HNE (K ety , J avoy , T hierry , J ulou and G lowinski , 1967), and increased tyrosine hydroxylase activity (M usacchio , J ulou , K ety and G lowinski , 1969) at 24 h after a series of two ECS daily for 7 days. Together, these data suggest a sustained activation of the 5-HT and/or NE systems following chronic ECS. We now report the results of a series of experiments in which some of the potential variables that may be involved in the MAO response were investigated and that indicate some biochemical specificity of the response. In these experiments, succinate dehydrogenase (SDH) activity was also assayed to assess possible nonspecific effects of repeated seizures on mitochondrial metabolism and catechol O -methyltransferase (COMT) activity was determined to see if this extracellular degradative enzyme for NE was affected in the same way as MAO located intracellularly in the mitochondria.