Effects of chronic treatment with ACTH on the intracellular levels of cyclic-AMP and cyclic-GMP in the rat adrenal cortex

Summary The effects of chronic ACTH treatment on the increase in the intracellular concentration of cyclic-AMP and cyclic-GMP acutely elicited by ACTH in the rat adrenal cortex were investigated. The results are consistent with the hypothesis that chronic ACTH treatment stimulates a) the de novo synthesis of adenylate- and guanylate-cyclase or b) the synthesis of new specific membrane receptors for ACTH.Part of this work was presented at the 3rd International Conference on Cyclic Nucleotides, July 1977, New Orleans, Abstr. Book, p. 79.     

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).     

Effects of chronic treatment with ACTH on the intracellular levels of cyclic-AMP and cyclic-GMP in the rat adrenal cortex.

The effects of chronic ACTH treatment on the increase in the intracellular concentration of cyclic-AMP and cyclic-GMP acutely elicited by ACTH in the rat adrenal cortex were investigated. The results are consistent with the hypothesis that chronic ACTH treatment stimulates a) the de novo synthesis of adenylate- and guanylate-cyclase or b) the synthesis of new specific membrane receptors for ACTH.     

Free amino acids in motor cortex of amyotrophic lateral sclerosis.

Free amino acids were estimated quantitatively in the motor cortex from 3 patients with amyotrophic lateral sclerosis (ALS) and 11 control subjects. Among 7 amino acids which showed statistically significant changes, taurine was the only one which was increased constantly and most markedly in the motor cortex of all the 3 ALS cases. It was suggested that the metabolism of sulfur amino acids might be affected in comparatively early stages of ALS.     

The activity of monoamine oxidases A and B in gamma-irradiated rabbit brains

Summary The activities of monoamine oxidases A and B towards 5-hydroxytryptamine and -phenethylamine, respectively, were compared in the left and right caudatus, hippocampus, parietal cortex, cerebellum and frontal cortex 6 months after gamma-irradiation (single dose of 23 Gy) of either the right hemisphere or of the whole rabbit brain (in which case, a dose of 16 Gy). No difference in monoamine oxidase A or B activities were found in any of the brain regions.Acknowledgment. This study was supported by grants from the Swedish Medical Research Council (12x–5664 and 04x–4145), Hansson's, Lion's, Mångberg's and Sundblad's funds.     

The cerebral cortex regulates immune responses in the mouse

Ablation of the left cerebral cortex abrogates the production of thymic hormone, reduces the number of spleen T cells and impairs immunization with sheep erythrocytes. In addition, partial decortication inhibits the ability of sodium diethyldithiocarbamate (DTC) to increase the level of circulating thymic hormone, as well as the number of splenic T cells. Therefore, the cerebral cortex would display an important role to maintain body integrity and relations with the external environment, through its effects on the immune system.     

DNA fragmentation in leukocytes following repeated low dose sarin exposure in guinea pigs

The objective of this study was to determine levels of DNA fragmentation in blood leukocytes and parietal cortex from guinea pigs following repeated lowlevel exposure to the chemical warfare nerve agent (CWNA) sarin. Guinea pigs were injected (s.c.) once a day for 10 days with saline, or 0.1, 0.2, or 0.4 LD₅₀ (50% mean lethal dose) sarin dissolved in sterile physiological saline. Blood and parietal cortex was collected after injection at 0, 3, and 17 days recovery and evaluated for DNA fragmentation using single-cell gel electrophoresis (Comet assay). Cells were imaged using comet analysis software and three parameters of DNA fragmentation measured: tail length, percent DNA in the tail, and tail moment arm. Repeated low-dose exposure to sarin produced a dose-dependent response in leukocytes at 0 and 3 days post-exposure. There was a significant increase in all measures of DNA fragmentation at 0.2 and 0.4 LD₅₀, but not at 0.1 LD₅₀. There was no significant increase in DNA fragmentation in any of the groups at 17 days post-exposure. Sarin did not produce a systematic dose-dependent response in parietal cortex at any of the time points. However, significant increases in DNA fragmentation at 0.1 and 0.4 LD₅₀ were observed at 0 and 3 days post-exposure. All measures of DNA fragmentation in both leukocytes and neurons returned to control levels by 17 days post-exposure, indicating a small and non-persistent increase in DNA fragmentation following repeated low-level exposure to sarin. Received 23 July 2007; received after revision 23 August 2007; accepted 3 September 2007 Research was conducted in compliance with the Animal Welfare Act, and other Federal statutes and regulation relating to animals and experiments involving animals and adheres to the principles stated in the Guide for the Care and Use of Laboratory Animals, NIH publication 85-23. The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense (para 4-3), AR 360–365.     

Effect of a steroid contraceptive, "Enidrel" on the pre- and postnatal development of rats

To determine the long-term effects of prolonged and intensive treatment with an anticonceptive steroid, 60 female Wistar rats were given 1 mg/kg/day Enidrel (norethynodrel plus ethinyl estradiol 3-methyl-ether) by gastric sound for 60 days. The animals were divided into 2 groups and were placed with males for 10 days. Group 1 continued to recieve Enidrel through mating to the 15th day of gestation; Group 2 received no further treatment. General behavior and weight of the animals was unchanged when compared with controls. There were profound disturbances in the estrous cycle, but couplings and number of impregnations were normal in both groups. Most of the females in Group 1 aborted normal fetuses between Gestation Days 8 and 15; those in Groups 2 continued to term. Group 1 animals were remated and siblings of the 1st generation were crossed. The animals were fertile and the ne onates developed normally. It is concluded that Enidrel had no effect on morphogenesis and no masculinization effect on the hypophyso-hypothalamic system, as evidenced by the normal sexual behavior and fertility of the females.     

Focal brain hyperthemia. I. The cerebellar cortex

Summary Focal brain hyperthemic methodology has been described and data presented on the cerebellum which show that enhancement of electrical activity of cerebellar cortex occurs when this method is used with careful monitoring of temperature. The duration of electrically induced cerebral after-discharges is shortened when cerebellar warming reaches 39.5–42.0°C. Since these effects are repeatable over many hours, there appears to be little, if any, resultant damage. Such induced changes in the cerebrum resemble those previously reported in which electrical stimuli were applied to the cerebellar cortex.We sincerely thank the United States Public Health Service for financial support from grant No. NS11929.     

Inhibition of steroidogenic activity in the adrenal cortex of rats fed benzene hexachloride (hexachlorocyclohexane)

Summary Feeding various dosages of benzene hexachloride (100, 250, 750 and 1500 ppm) in the diet to weanling male albino rats for 90 days resulted in marked hypertrophy of the adrenals with large, vacuolated cells in the cortex at 750 and 1500 ppm. Accumulation of cholesterol-positive lipids and marked reduction in the activities of steroidogenic enzymes such as ⁵ 3 HSDH, 11 HSDH, G-6-PDH and SDH were seen using histochemical methods in the adrenal cortex of rats fed 750 and 1500 ppm. The results are suggestive of steroidogenic inhibition at 750 and 1500 ppm of dietary BHC while 100 and 250 ppm did not produce any discernible changes in the adrenal cortex.Acknowledgments. The authors thank Dr Muralidhara, H.P. Ramesh and K. Nanjundiah for their help and Prof. H.B. Devaraj Sarkar, Department of Zoology, University of Mysore, for providing us facilities for histochemical work. We are grateful to Sri C.P. Natarajan, for his keen interest in this investigation.     

Cell lineage and cell migration in the developing cerebral cortex

Summary Modern techniques which trace lineages of individual progenitor cells have provided some clues about the processes that determine cell fate in the brain, and have also given us some information about migratory patterns of clonally related cells. In many parts of the central nervous system, progenitors are multipotent; single clones can contain multiple neuronal types or even mixtures of neurons and glia. In addition, one can observe a wide distribution in clone size, even when marking is done in a narrow time window. This suggests that progenitor cells may be fairly plastic and responsive to environmental signals. In the developing cortex, clonally related cells are initially grouped near each other, as in the retina and tectum. However, the subsequent migration of these cells from the ventricular zone to the cortex along glial fibers is accompanied by a progressive dispersion of clonally related neurons.     

Characterization of the role of metallothionein-3 in an animal model of Alzheimer’s disease

Among the dementias, Alzheimer’s disease (AD) is the most commonly diagnosed, but there are still no effective drugs available for its treatment. It has been suggested that metallothionein-3 (MT-3) could be somehow involved in the etiology of AD, and in fact very promising results have been found in in vitro studies, but the role of MT-3 in vivo needs further analysis. In this study, we analyzed the role of MT-3 in a mouse model of AD, Tg2576 mice, which overexpress human Amyloid Precursor Protein (hAPP) with the Swedish mutation. MT-3 deficiency partially rescued the APP-induced mortality of females, and mildly affected APP-induced changes in behavior assessed in the hole-board and plus-maze tests in a gender-dependent manner. Amyloid plaque burden and/or hAPP expression were decreased in the cortex and hippocampus of MT-3-deficient females. Interestingly, exogenously administered Zn₇MT-3 increased soluble Aβ40 and Aβ42 and amyloid plaques and gliosis, particularly in the cortex, and changed several behavioral traits (increased deambulation and exploration and decreased anxiety). These results highlight that the control of the endogenous production and/or action of MT-3 could represent a powerful therapeutic target in AD.     

The endocannabinoid system in rat gliosomes and its role in the modulation of glutamate release

The endocannabinoid system and endocannabinoid receptor-driven modulation of glutamate release were studied in rat brain cortex astroglial gliosomes. These preparations contained the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, as well their major biosynthetic (N-acyl-phosphatidylethanolamines-hydrolyzing-phospholipase D and diacylglycerol-lipase) and catabolic (fatty acid amide-hydrolase and monoacylglycerol-lipase) enzymes. Gliosomes expressed type-1 (CB1R), type-2 (CB2R) cannabinoid, and type-1 vanilloid (TRPV1) receptors, as ascertained by Western blotting and confocal microscopy. Methanandamide, a stable analogue of anandamide acting as CB1R, CB2R, and TRPV1 agonist, stimulated or inhibited the depolarization-evoked gliosomal [³H]d-aspartate release, at lower and higher concentrations, respectively. Experiments with ACEA (arachidonyl-2′-chloroethylamide), JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]-pyran) and capsaicin, selective agonists at CB1R, CB2R and TRPV1, respectively, demonstrated that potentiation of [³H]d-aspartate release was due to CB1R while inhibition to CB2R and TRPV1 engagement. These findings were confirmed by using selective receptor antagonists. Furthermore, CB1R activation caused increase of intracellular IP3 and Ca²⁺ concentration, suggesting an involvement of phospholipase C.     

Dopamine and cerebral cortical blood flow in the rat

Summary Dopamine topically applied to the cerebral cortex (1–20 g/ml) or administered i.v. (0.5–64 g/kg/min) has no effects on cerebral cortical blood flow in the rat.     

D-ala2-Metenkephalinamide blocks the synaptically elicited cortical spreading depression in rats

Summary Spreading depression (SD) was elicited in rats anesthetized with pentobarbital by a train of 8 electrical pulses (0.1 ms, 10 Hz) applied to parietal cortex. Local application of 50 g of D-ala²-metenkephalinamide (DAME) on the stimulated area evoked one or two SD waves followed by an increase of SD threshold from 40 V to 90 V. This effect could be partly prevented by naloxone (1 mg/kg i.p.) and reversed by local application of 4-aminopyridine (10^–3 M, 2 l), which reduced SD threshold to 5 and 20 V in normal and DAME-treated cortex, respectively. It is argued that DAME exerts an inhibitory effect on cortical neurons and that the initial SD facilitation is due to initial blockade of inhibitory neurons in the superficial cortical layers.supported by the European Training Program in Brain and Behavior Research.     

Testing for the usefulness of forecasts

Ashley (Journal of Forecasting 1983; 2 (3): 211–223) proposes a criterion (known as Ashley's index) to judge whether the external macroeconomic variables are well forecast to serve as explanatory variables in forecasting models, which is crucial for policy makers. In this article, we try to extend Ashley's work by providing three testing procedures, including a ratio‐based test, a difference‐based test, and the Bayesian approach. The Bayesian approach has the advantage of allowing the flexibility of adapting all possible information content within a decision‐making environment such as the change of variable's definition due to the evolving system of national accounts. We demonstrate the proposed methods by applying six macroeconomic forecasts in the Survey of Professional Forecasters. Researchers or practitioners can thus formally test whether the external information is helpful. Copyright © 2010 John Wiley & Sons, Ltd.     

Free amino acids in motor cortex of amyotrophic lateral sclerosis

Summary Free amino acids were estimated quantitatively in the motor cortex from 3 patients with amyotrophic lateral sclerosis (ALS) and 11 control subjects. Among 7 amino acids which showed statistically significant changes, taurine was the only one which was increased constantly and most markedly in the motor cortex of all the 3 ALS cases. It was suggested that the metabolism of sulfur amino acids might be affected in comparatively early stages of ALS.Acknowledgments. The authors are grateful to Dr M. Uono, Department of Neurology, Tokyo Metropolitan Hospital of Fuchu, and Dr K. Hirayama, Department of Neurology, Brain Research Institute, School of Medicine, Chiba University, for their generous cooperation.     

D-ala2-Metenkephalinamide blocks the synaptically elicited cortical spreading depression in rats

Spreading depression (SD) was elicited in rats anesthetized with pentobarbital by a train of 8 electrical pulses (0.1 ms, 10 Hz) applied to parietal cortex. Local application of 50 micrograms of D-ala2-metenkephalinamide (DAME) on the stimulated area evoked one or two SD waves followed by an increase of SD threshold from 40 V to 90 V. This effect could be partly prevented by naloxone (1 mg/kg i.p.) and reversed by local application of 4-aminopyridine (10(-3) M, 2 microliters), which reduced SD threshold to 5 and 20 V in normal and DAME-treated cortex, respectively. It is argued that DAME exerts an inhibitory effect on cortical neurons and that the initial SD facilitation is due to initial blockade of inhibitory neurons in the superficial cortical layers.     

Intrathalamic sensory connections mediated by the thalamic reticular nucleus

The thalamus and cerebral cortex are linked together to form a vast network of interconnections. Different modes of interactions among the cells in this network underlie different states of consciousness, such as wakefulness and sleep. Interposed between the dorsal thalamus and cortex are the GABAergic neurons of the thalamic reticular nucleus (TRN), which play a pivotal role not only in switching between the awake and sleep states but also in sensory processing during the awake state. The visual, somatosensory, and auditory sectors of TRN share many of the same organizational features. Each of these sectors contains maps, which are related to its inputs and outputs, and organizational components called ‘slabs.’ It is proposed that, during wakefulness, TRN is crucially involved in resetting the activity levels in sensory nuclei of the dorsal thalamus, which allows the cortex to actively and periodically compare its on-going sensory processing with the available sensory information. Received 11 May 1999; received after revision 15 July 1999; accepted 21 July 1999     

Focal brain hyperthermia. I. The cerebellar cortex

Focal brain hyperthermic methodology has been described and data presented on the cerebellum which show that enhancement of electrical activity of cerebellar cortex occurs when this method is used with careful monitoring of temperature. The duration of electrically induced cerebral after-discharges is shortened when cerebellar warming reaches 39.5--42.0 degrees C,. Since these effects are repeatable over many hours, there appears to be little, if any, resultant damage. Such induced changes in the cerebrum resemble those previously reported in which electrical stimuli were applied to the cerebellar cortex.