Evidence for a direct action of monamines on the chick central nervous system

Zusammenfassung Pharmakologische Untersuchungen im Hinblick auf eine eventuelle Wechselwirkung von psychotropen Pharmaka und biogenen Aminen ergaben: (1) offenbares Eindringen von 5-HT, DA und NE in das Zentralnervensystem junger Hühner. (2) Schlafcharakteristisches Verhalten von EEG und Verhaltensweise nach Verabreichung von 5-HT und NE. (3) Auftreten der ?arousal?-Charakteristika mit anf?nglicher Akinese im EEG und Verhalten nach Dopamin- oder Dopazufuhr.

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Supported by U.S.P.H.S. Grant No. 5 TI MH-6415.     

Guaiacol-O-methyltransferase: A mammalian enzyme capable of forming di-O-methyl catecholamine derivatives

Résumé On a extrait et characterisé une enzyme capable de transférer aux catécholamines 4-O-méthyles le group méthyle provenant de l'S-adénosylméthionine et produire des substances diméthoxyques. Cette enzyme est active dans différents tissus de Mammifères.

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This work was supported by Public Health Service grants Nos. MH-08618 and MH-07961 and a Research Scientist's Award No. MH-14020, to A.J.F.     

Changes in activity and hormonal sensitivity of brain adenyl cyclase following chronic ethanol administration

Zusammenfassung Nachweis, dass durch langdauernde Äthanol-Zufuhr die Adenyl-Zyklase-Aktivität in der Grosshirnrinde von Mäusen vermehrt wird, während die fermentative Aktivität bei der akuten Zufuhr sich nicht verändert. Die Empfindlichkeit der Adenyl-Zyklase-Aktivität auf Norepinephrin im Mäusegehrin ist nach dieser Äthanol-Zufuhr deutlich herabgesetzt.

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Supported in part by grants No. MH-18663 and MH-16477 from USPHS, to whom reprint requests have to be sent.     

Adrenal dopamine-β-hydroxylase activity: 24-hour rhythmicity and evidence for pineal control

Summary Adrenal medullary dopamine--hydroxylase activity was found in male rats to have a 24-hour rhythm, with an approximately 6-fold increase at about the time of the onset of darkness. This nocturnal rise in enzyme activity did not occur when lights were kept on, nor did it occur in animals that had been pinealectomized.Supported in part by grants from the Ford Foundation (No. 630-05050A), National Institutes of Health (No. HD-03352) and National Institute of Mental Health (No. MH-25019) USPHS.     

Modulation of dopaminergic transmission by alpha-noradrenergic agonists and antagonists: Evidence for antidopaminergic properties of some alpha antagonists

Summary The effects on dopamine (DA) metabolism, on³H-spiperone binding and on amphetamine-induced stereotypies of a variety of drugs with different actions on alpha₁-and alpha₂-noradrenergic (NA) receptors have been investigated.The preferential alpha₂-antagonists yohimbine, rauwolscine, piperoxane and esproquin as well as the preferential alpha₁-antagonists corynanthine and WB4101 increased homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum, mesolimbic area, and cortex. Prazosine and clonidine tended to reduce HVA and DOPAC. The preferential alpha₂-antagonists, tolazoline and RX-781094A, had no measurable effects on DA metabolism even at high doses.Those compounds which in comparable doses increased DA metabolism inhibited³H-spiperone binding in the hippocampus. The effects in the striatum and cortex were smaller and did not show a relation to those in hippocampus or on DA metabolism. Only the yohimbine alkaloids antagonized amphetamine-induced stereotypies.The results suggest that the effects on DA metabolism at least of yohimbine, rauwolscine, and corynanthine are related to their intrinsic antidopaminergic properties. The same might be true, although with a lesser degree of certainty, for piperoxane, esproquin, and WB4101.Since many of the tested compounds possessing alpha-antagonistic properties interacted with the DA system, a close molecular relationship between alpha-noradrenergic and DA receptors might be anticipated. The preference of these compounds for the hippocampal subtype of DA receptors might indicate a particular role of the latter in the regulation of DA metabolism. On the other hand, the antagonism against haloperidol's enhancing effect on DA metabolism by clonidine suggests a modulatory NA influence on DA transmission. The observation that clonidine reduced the effects of yohimbine and piperoxane to a lesser degree than that of haloperidol, is in agreement with this notion.Part of this work has been presented at the 13th Meeting of the Union of Swiss Societies of Experimental Biology, Lausanne, March 26/27. 1981 (for abstract see Waldmeier and Bischoff, 1981).     

Effect of brocresine on conditioned avoidance behavior in mice

Summary Brocresine, an inhibitor of brain histamine biosynthesis, has been found to impair the ability of mice to avoid shock in a shuttle box CAR test; escape performance was unaffected in these studies.Supported in part by USPHS Grants Nos. MH-22570 and NS-10203. Brocresine dihydrogen phosphate was kindly provided by Lederle Laboratories.     

Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production

Intracellular accumulation of α-synuclein (α-syn) are hallmarks of synucleinopathies, including Parkinson’s disease (PD). Exogenous addition of preformed α-syn fibrils (PFFs) into primary hippocampal neurons induced α-syn aggregation and accumulation. Likewise, intrastriatal inoculation of PFFs into mice and non-human primates generates Lewy bodies and Lewy neurites associated with PD-like neurodegeneration. Herein, we investigate the putative effects of synthetic human PFFs on cultured rat ventral midbrain dopamine (DA) neurons. A time- and dose-dependent accumulation of α-syn was observed following PFFs exposure that also underwent phosphorylation at serine 129. PFFs treatment decreased the expression levels of synaptic proteins, caused alterations in axonal transport-related proteins, and increased H2AX Ser139 phosphorylation. Mitochondrial impairment (including modulation of mitochondrial dynamics-associated protein content), enhanced oxidative stress, and an inflammatory response were also detected in our experimental paradigm. In attempt to unravel a potential molecular mechanism of PFFs neurotoxicity, the expression of inducible nitric oxide synthase was blocked; a significant decline in protein nitration levels and protection against PFFs-induced DA neuron death were observed. Combined exposure to PFFs and rotenone resulted in an additive toxicity. Strikingly, many of the harmful effects found were more prominent in DA rather than non-DA neurons, suggestive of higher susceptibility to degenerate. These findings provide new insights into the role of α-syn in the pathogenesis of PD and could represent a novel and valuable model to study DA-related neurodegeneration.     

Blood citric acid cycle and individual response to morphine analgesia in rats

Zusammenfassung Es konnte gezeigt werden, dass bei Ratten eine Beziehung besteht zwischen der analgetischen Wirkung von Morphin und den Blut-Konzentrationen einiger Metaboliten des Krebs-Zyklus.

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This work was supported by grant No. MH-06564, NIMH.     

Synaptic development in brains of rats exposed perinatally to ethanol

Summary Development of brain synaptosomal uptakes of³H-norepinephrine and³H-dopamine in pups whose mothers received ethanol were nearly normal. However, development of synaptosomal uptake of³H-serotonin was significantly lower than in controls, while uptake of³H-norepinephrine into synaptic storage vesicles was increased.The authors thank F.J. Seidler and W.L. Whitmore for their technical assistance. Research was supported by U.S. Public Health Service grants AA-02935 and DA-00465. TAS is recipient of Research Scientist Development Award DA-00006 from the National Institute on Drug Abuse, and SMS is recipient of Research Scientist Award MH-06489 from the National Institute of Mental Health.     

Interaction of CDP-choline with synaptosomal transport of biogenic amines and their precursors in vitro and in vivo in the rat corpus striatum.

Added to a striatal synaptosomal homogenate of rat brain, CDP-choline 10(-4) M inhibits the uptake of norepinephrine (NE), dopamine (DA) and serotonin (5 HT) in a competitive fashion and enhances the uptake of tyrosine and tryptophan; administered to animals, CDP-choline (50 mg/kg/l h/i.v.) inhibits only the in vitro uptake of DA but enhances the uptake of precursors.     

Ethanol reduces Ca2+ concentrations in arterial and venous smooth muscle

Summary The present results, using isolated rat aortic strips and portal vein segments, demonstrate that ethanol (170–430 mM) significantly inhibits calcium uptake in these 2 different types of vascular smooth muscle.Supported by NIH grant No. HL-18015 and NIMH grant No. MH-26236. Request for reprints should be addressed to B.M. Altura.     

Interaction of CDP-choline with synaptosomal transport of biogenic amines and their precursors in vitro and in vivo in the rat corpus striatum

Summary Added to a striatal synaptosomal homogenate of rat brain, CDP-choline 10^–4 M inhibits the uptake of norepinephrine (NE), dopamine (DA) and serotonin (5 HT) in a competitive fashion and enhances the uptake of tyrosine and tryptophan; administered to animals, CDP-choline (50 mg/kg/l h/i.v.) inhibits only the in vitro uptake of DA but enhances the uptake of precursors.This research was supported by CNRS grant (ERA No. 560) and Inserm grant (FRA 5).     

Effect of clonidine on the noradrenergic cyclic AMP generating system in the limbic forebrain and on medial forebrain bundle self-stimulation behavior

Summary The present results show that clonidine does not mimic the agonist action of norepinephrine (NE) on the noradrenergic cyclic AMP generating system of the limbic forebrain, but antagonizes the stimulatory effect of NE while not influencing the action of isoprenaline. In self-stimulation behavior, clonidine decreases responding and blocks the facilitation caused by d-amphetamine.Supported by USPHS grant MH-11468 and the Tennessee Department of Mental Health and Mental Retardation. We are grateful to Boehringer, Ingelheim, for the generous supply of clonidine HCl.     

Protracted analgesia in young and adult rats maternally exposed to methadone

Summary The analgesic response to the hot-plate test was studied in 21-, 45-, 60-, 120- and 300-day-old rats maternally exposed to methadone (5 mg/kg). An elevation in nociceptive threshold, in the absence of further exposure to methadone, was observed in young and adult rats perinatally subjected to methadone.This research was supported by grant DA 01618.     

Seasonal changes in the uptake capacity of the suprachiasmatic nucleus for3H-serotonin

Summary The suprachiasmatic nucleus, a hypothalamic center important in mediation of circadian and estrous cycles, is shown in adult rats to have seasonal changes in its uptake capacity in vitro for³H-serotonin.Supported in part by grants from the National Institute of Mental Health (MH-25091), the National Institute of Health (HD-10263, HD-03352, 5-T01-HD00104-10), USPHS, and the Ford Foundation (grant No. 630-0505 B, C).     

Absence of dopamine sensitive adenylate cyclase in the A10 region, the origin of mesolimbic dopamine neurones.

Dopamine (DA) failed to stimulate the adenylate cyclase of the mesolimbic A10 DA nerve cell body area, in contrast to tis activating effect in the nigrostriatal A9 DA cell body area. The enzyme was stimulated by GMPPNP (a GTP analog) and NaF. This indicates the absence in the A 10 cell area of DA receptors with functional coupling on adenylate cyclase, in contrast to the A9 cell area where such DA receptors are believed to be located on afferent axon terminals.     

Anamnestic response to an opioid

Zusammenfassung In Mäusen entsteht eine Toleranz gegen den kataraktogenen Effekt einer Einzeldosis von Opioid. Werden fraktionierte Dosen gegeben, so entwickelt sich jedoch eine weitaus grössere Toleranz, wofür eine Sensibilisierung als Ursache angenommen wird.

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Supported by a grant No. MH-12988-05 from the United States Public Health Service.     

Long-term depressor effects of catecholamine neuronal grafts in the third ventricle of the brain in normotensive rats

Neuronal tissue containing A-6 group noradrenalin (NA) neurons of the locus ceruleus, or A-10 group dopamine (DA) neurons of the substantia nigra, was grafted into the third ventricle at the level of the preoptic-anterior hypothalamic region, in normotensive male rats. A significant and long-lasting depressor effect was shown in rats with either graft. In rats with an NA neuron-rich graft, plasma concentrations of arginine-vasopressin (AVP), plasma renin activity (PRA), and corticosterone (CS) decreased significantly, whereas in rats with a DA neuron-rich graft, AVP and PRA concentrations also decreased significantly but CS showed no significant change. Neither NA nor adrenalin in plasma changed significantly in rats with either graft.     

Long-term depressor effects of catecholamine neuronal grafts in the third ventricle of the brain in normotensive rats

Summary Neuronal tissue containing A-6 group noradrenalin (NA) neurons of the locus ceruleus, or A-10 group dopamine (DA) neurons of the substantia nigra, was grafted into the third ventricle at the level of the preoptic-anterior hypothalamic region, in normotensive male rats. A significant and long-lasting depressor effect was shown in rats with either graft. In rats with an NA neuron-rich graft, plasma concentrations of arginine-vasopressin (AVP), plasma renin activity (PRA), and corticosterone (CS) decreased significantly, whereas in rats with a DA neuron-rich graft, AVP and PRA concentrations also decreased significantly but CS showed no significant change. Neither NA nor adrenalin in plasma changed significantly in rats with either graft.