Protein metabolism in the brain.
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Animals↗
Biomedical subjects
A Lajtha
Publications and source records attributed to A Lajtha.
Peroxidative stress effects on calpain activity in brain of young and adult rats.
Three hours after administration of the pro-oxidant 2-cyclohexen-1-one, calpain activity was significantly reduced in the brain of young rats, but not in the brain of adult rats, and cathepsin D activity remained unchanged. Addition of isovalerylcarnitine to the incubation medium increased calpain activity 5-7-fold, counteracting the effect of the pro-oxidant.
Aging↗
Regional distribution of glutamate and aspartate in adult and old human brain.
In previous studies on rat brain we found that the observed heterogeneity of the regional distribution of amino acids was much greater when small well-defined anatomical structures were assayed. We therefore reinvestigated the distribution of glutamate and aspartate in 50 discrete areas from adult and old human brain. The concentration of glutamate in the area of highest level was 4.5 and 4.7 times as high as in the area of lowest level in adult and old brain respectively; for aspartate these values were 3.0 and 6.6. Several changes in old brain were noted. The human pattern differed from that in rat.
Adult↗
Acetyl-L-carnitine releases dopamine in rat corpus striatum: an in vivo microdialysis study.
The effect of acetyl-L-carnitine, a compound reported to be beneficial for senile patients, on the release of dopamine (DA) from the striatum was studied by using in vivo brain dialysis in anesthetized rats coupled with HPLC-electrochemical detection. Striatal infusion of acetyl-L-carnitine increased the efflux of DA with no apparent changes in efflux of DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA). The DA-releasing effect of acetyl-L-carnitine was concentration- and Ca(2+)-dependent, and was abolished by omega-conotoxin fraction GVIA and tetrodotoxin, inhibitors of the voltage-dependent Ca2+ and Na+ channels, respectively. Nomifensine, an inhibitor of DA reuptake did not alter the DA-releasing property of acetyl-L-carnitine. DA released from the striatum by acetyl-L-carnitine was decreased by reserpine pretreatment whereas the d-amphetamine-evoked DA outflow was not affected. In contrast to acetyl-L-carnitine, d-amphetamine reduced the extracellular concentrations of DOPAC and HVA. We conclude from the present data that acetyl-L-carnitine evokes DA release from the vesicular pools of the nigrostriatal dopaminergic neurons by a Ca(2+)-dependent, exocytotic process.
Acetylcarnitine↗
Animal models for human diseases of the brain.
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Animals↗
Decreased brain N-acetylaspartate in Huntington's disease.
The concentration of N-acetylaspartic acid (NAA) was measured in perchloric acid extracts of postmortem brain tissue obtained from patients with Huntington's disease and from control subjects. The material in the desalted extracts was resolved on an ion exclusion column and the content of NAA was determined by subsequent fluorometric quantitation of aspartate in hydrolyzates of the resolved NAA. The concentration of NAA in the putamen from patients with Huntington's disease was less than half that of controls (2.74 vs. 6.06 mumol/g wet weight). A smaller but significant reduction was also evident in samples of cerebral cortex from Brodmann area 10 (3.99 vs. 5.29 mumol/g), while the difference in concentrations in the cerebellum was not statistically significant. Though NAA could play a direct role in Huntington's disease, it seems more likely that the changes observed reflect illness or death of neurons, and that it may be feasible to monitor the course of Huntington's disease from NAA determinations. The same tissue extracts were also examined for the presence of D-isomers of amino acids. Only traces were found in NAA, aspartate, or glutamate.
Aspartic Acid↗
Motor activity and the mesotelencephalic dopamine function. I. High-resolution temporal and genetic analysis of open-field behavior.
In a genetic selection experiment whose goal was to construct congenic neurological animal model lines with different mesotelencephalic dopamine systems, we produced foundation F2 generations derived from crosses (C57BL/6ByJXBALB/cJ and C57BL/6ByJXCXBI/ByJ) between highly inbred mouse lines with different dopamine systems. In this report, temporal distribution, latency, and genetic variability of open-field (OF) behavioral variables were investigated in order to establish a behavioral profile for the various generations and to provide behavioral data as a first step towards multivariate studies on correlations between OF behaviors and mesencephalic and striatal tyrosine hydroxylase activity. Analysis of the behavioral data provided evidence that measures of the open-field behaviors varied significantly across time segments of the test and that the temporal profiles of several behavioral variables were genotype-dependent. It is suggested that (1) OF behaviors have dynamic temporal profiles, and (2) temporal-genetic analysis can be a useful auxiliary method in the functional interpretation of behavior.
Animals↗
Motor activity and the mesotelencephalic dopamine function. II. Multivariate analysis of genetically segregating generations.
Previous experiments on genetically different inbred strains of mice demonstrated parallel variations between the activity of regional brain tyrosine hydroxylase (TH) and locomotor behavior. Based on these associations, it was hypothesized that genetic variations in mesotelencephalic TH activity, an index of dopamine neurotransmitter function, would correlate positively with exploratory and locomotor behavior. In order to test this hypothesis, open-field motor behaviors and mesencephalic and striatal TH activities were analyzed by multivariate statistical methods in genetically segregating (C57BL/6ByJ X BALB/cJ)F2 and (C57BL/6ByJ X CXBI/ByJ)F2 generations. Factor analysis, based on correlation matrices of variables with significant genetic dominance or additive effects, demonstrated that locomotor activity and frequency of occurrence of various motor patterns were not correlated with mesencephalic and striatal TH activity. These results indicate that the assumption of a positive phenotypic correlation between spontaneous motor activity and mesotelencephalic TH activity does not hold in genetically segregating populations. Strategies and problems in revealing the behavioral consequences of genetically based variations in the mesotelencephalic DA system are briefly discussed.
Analysis of Variance↗
Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid.
We studied the effect of local administration of nicotine on the release of monoamines in striatum, substantia nigra, cerebellum, hippocampus, cortex (frontal, cingulate), and pontine nucleus and on the release of glutamic acid in striatum of rats in vivo, using microdialysis for nicotine administration and for measuring extracellular amine and glutamic acid levels. Following nicotine administration the extracellular concentration of dopamine increased in all regions except cerebellum; serotonin increased in cingulate and frontal cortex; and norepinephrine increased in substantia nigra, cingulate cortex, and pontine nucleus. Cotinine, the major nicotine metabolite, had no effect at similar concentrations. The cholinergic antagonists mecamylamine and atropine, the dopaminergic antagonists haloperidol and sulpiride, and the excitatory amino acid antagonist kynurenic acid all inhibited the nicotine-induced increase of extracellular dopamine in the striatum. The fact that kynurenic acid almost completely prevented the effects of nicotine, and nicotine at this concentration produced a 6-fold increase of glutamic acid release, suggests that the effect of nicotine is mainly mediated via glutamic acid release.
Animals↗
Dietary manipulation with high marine fish oil intake of fatty acid composition and arachidonic acid metabolism in rat cerebral microvessels.
Male weanling Wistar rats were maintained on one of two semisynthetic diets, differing only in the type of oil used: (i) 10% by weight marine fish oil (MFO group) containing 20% eicosapentaenoic acid (EPA) and 17% docosahexaenoic acid (DHA), or (ii) 10% by weight sunflower oil (SFO group). The control group was kept on standard diet for 4 weeks. Blood-free microvessels were isolated from brain cortex by a rapid micromethod, and their fatty acid composition was determined by gas chromatography. It was found that the proportion of n-3 fatty acids (including EPA and DHA) increased significantly in the microvessels of the MFO group, accompanied by a decrease of the n-6 fatty acid series. The changes in fatty acid composition of endothelial cells were not significant in the SFO group in comparison to the control. The amounts of lipoxygenase and cyclooxygenase metabolites were determined. Dietary fish oil decreased the percentage of total products of arachidonate by 50%, while the SFO diet had no effect on it. The amount of lipoxygenase products in the MFO group decreased significantly from 16931 +/- 3131 dpm to 6399 +/- 357 dpm/300 mg wet weight of brain. Significantly less PGF-1 alpha, PGF-2 alpha and 12-hydroxyheptadecatrienoic acid (HHT) were found in the capillaries of MFO treated animals, in comparison to the SFO group. The ratios of vasoconstrictor and vasodilator metabolites of arachidonate cascade were not modified by the diets. Our results suggest that fish oil diet reduces the arachidonate cascade in cerebral microvessels. This effect may explain for the efficiency of n-3 fatty acids in vascular diseases.
6-Ketoprostaglandin F1 alpha↗
N-type calcium channels are involved in the dopamine releasing effect of nicotine.
Mouse striatum was incubated with [3H]dopamine ([3H]DA) and superfused with and the tritium efflux induced by nicotine, electrical stimulation, or simultaneous nicotine and electrical stimulation was measured, to characterize the role of different Ca2+ channels in the transmitter release. Nicotine stimulation and electrical stimulation exerted additive effects on tritium efflux. Separation of the released radioactivity on alumina columns indicated that nicotine or electrical stimulation increases the release of [3H]DA and that the outflow of 3H-labeled metabolites was similar with the two different stimulation procedures. Removal of Ca2+ from the superfusate resulted in a marked reduction in the tritium release evoked by nicotine, whereas the electrical stimulation-evoked tritium release was completely dependent on external Ca2+. The L- and N-type calcium channel blockers omega-conotoxin GVIA and Cd2+ inhibited the tritium release from the striatum evoked by either nicotine or electrical stimulation, whereas the L-type and T-type channel blockers diltiazem and Ni2+ did not alter release of [3H]DA. We conclude that N-type voltage-sensitive Ca2+ channels participate in striatal dopamine release, and we speculate that nicotinic receptor-operated ion channels permeable to cations such as Ca2+ and N-type voltage-sensitive calcium channels may simultaneously open up, and they additively increase free intracellular Ca2+ concentration.
Analysis of Variance↗
Different effects of hypothermia on amino acid incorporation and on amino acid uptake in the brain in vivo.
The temperature dependence of the incorporation of amino acids into cerebral proteins and that of the transport of amino acids through the blood-brain barrier were studied. We measured the protein synthesis rate in vivo over a wide temperature range (14 degrees C-38 degrees C) in male Sprague-Dawley rats using a flooding dose of labeled valine. There was a linear dependence of the protein synthesis rate on temperature. The temperature quotient expressed as per cent decrease per 1 degree C was somewhat lower at the lower temperatures, a decrease from 7.8% in the 37.7-32.5 degrees C range to 6.7% in the 25.5-14 degrees C range. The transport of the three amino acids phenylalanine, lysine, and alanine, representing three transport systems, through the blood-brain barrier showed no temperature dependence in vivo. The results show that in hypothermia cerebral metabolic rates are lowered to a great extent, while some aspects of metabolic transport are not affected.
Alanine↗
Ibogaine antagonizes cocaine-induced locomotor stimulation in mice.
Ibogaine (40 mg/kg i.p.), when given 2 hours before an acute injection of cocaine (25 mg/kg s.c.) to C57BL/6 mice, reduced the cocaine-induced locomotor stimulation. Such stimulation was also reduced in the ibogaine-treated mice when a second injection of cocaine was given 24 hr later. Thus, the reduction in locomotor activity was not just the short-term depression of locomotor activity seen after ibogaine administration. When mice were given a daily injection of cocaine for 3 days and ibogaine was given after the cocaine injection on day 3, and again on day 4, cocaine-induced locomotor activity was reduced three hours later on day 4. On days 5 and 9 of the cocaine administration, with no further ibogaine treatment ambulatory counts were still lower in the ibogaine-pretreated mice. Locomotor stimulation induced by amphetamine (10 mg/kg) was not affected by ibogaine. An acute injection of ibogaine resulted in a transient increase in turnover of dopamine, as indicated by the increase in the ratio of metabolites of the dopamine to dopamine, followed by a decrease in the metabolites in striatum and frontal cortex 24 hr later. In vivo treatment with ibogaine did not affect the binding of [3H]WIN 35,248 to the cocaine binding site in striatal tissue measured in vitro. In addition, ibogaine added in vitro had a weak affinity to the WIN 35,248 binding site (IC50 for cocaine = 120 nM and for ibogaine = 1,500 nM). The results suggest that ibogaine may have induced a selective change in the dopaminergic system that results in a decrease in responsiveness to cocaine that persisted for at least 1 week.
Amphetamine↗
Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats.
The effect of ibogaine hydrochloride on locomotor stimulation induced by d-amphetamine sulfate was tested in male C57BL/6By mice and in female Sprague-Dawley rats. In mice, locomotor stimulation induced by d-amphetamine at 1 or 5 mg/kg s.c. was reduced by prior administration of one or two injections of ibogaine (40 mg/kg), given 2 or 18 hours earlier. This reduction in locomotor activity persisted for two days. Locomotor stimulation induced by a higher dose (10 mg/kg) of d-amphetamine was not reduced by such prior administration of ibogaine. A lower dose of ibogaine (20 mg/kg) did not reduce the subsequent locomotor activity induced by d-amphetamine. Ibogaine decreased striatal dopamine levels, while d-amphetamine increased them. Ibogaine treatment (2 x 40 mg/kg, 18 hours apart) induced a decrease by 30% in the level of striatal dopamine and its metabolites measured in tissue extracts 3 hours after the second ibogaine injection. One hour after d-amphetamine (5 mg/kg) administration, the level of striatal dopamine increased by 26%. Although the level of striatal dopamine was initially lower in the ibogaine-pretreated mice, d-amphetamine (5 mg/kg) administration induced an increase in striatal dopamine and its metabolites. The effect of ibogaine seems to be species specific, since in rats pretreated with ibogaine 18 hours before d-amphetamine, locomotor stimulation induced by d-amphetamine was further increased. In addition, the in vitro electrical-evoked release of [3H]dopamine from striatal tissue was either unchanged or inhibited in the presence of d-amphetamine, and after ibogaine pretreatment in vivo, the release of tritium in the presence of d-amphetamine was inhibited or stimulated in mice and rats, respectively.
3,4-Dihydroxyphenylacetic Acid↗
Regulatory interactions among axon terminals affecting the release of different transmitters from rat striatal slices under hypoxic and hypoglycemic conditions.
An in vitro model of ischemia was utilized to study the effects of both oxygen and glucose depletion on transmitter release from rat striatal slices. The spontaneous and stimulation-evoked releases of tritiated dopamine, gamma-aminobutyric acid, glutamate, and acetylcholine were measured. Hypoxia increased the evoked release of glutamate and dopamine without effect on the resting release. In contrast, hypoglycemia itself increased the resting release of dopamine. Hypoxia in combination with hypoglycemia provoked a massive release of glutamate, dopamine, and gamma-aminobutyric acid. The effect on acetylcholine release was less pronounced. Ca2+ withdrawal partly reduced the effect of hypoxia combined with hypoglycemia on dopamine release and application of tetrodotoxin (1 microM) abolished it. MK-801 (3 microM), an N-methyl-D-aspartate receptor antagonist, attenuated the effect of hypoxia and hypoglycemia on [3H]dopamine release. omega-Conotoxin (0.1 microM) had a similar effect on stimulation-evoked release under a hypoxic condition. The D2 receptor antagonist sulpiride (100 microM) failed to enhance the release of [3H]acetylcholine in hypoxia combined with hypoglycemia. It was suggested that in response to hypoxia combined with hypoglycemia there is a massive release of glutamate due to the increased firing rate which in turn releases dopamine from the axon terminals through stimulation of presynaptic N-methyl-D-aspartate receptors. Dopaminergic inhibitory control on ACh release seems not to be operative under conditions of hypoxia combined with hypoglycemia.
Animals↗
Dopamine efflux from striatum after chronic nicotine: evidence for autoreceptor desensitization.
We examined the effect of chronic nicotine treatment on dopaminergic activity by measuring the effects of D1 and D2 dopamine (DA) receptor agonists and antagonists on tritium release from mouse striatum preloaded with [3H]DA. The radioactivity released during superfusion was separated on alumina columns and the distribution and efflux of [3H]DA and its main 3H-labeled metabolites were quantified. After preloading by incubation with [3H]DA, the electrical stimulation-evoked tritium overflow was higher in striatum prepared from nicotine-treated mice, whereas in vitro addition of nicotine caused a similar increase in tritium release from striatum of untreated and chronic nicotine-treated mice. The overflow of [3H]DA and its 3H-metabolites exhibited similar distribution patterns in [3H]DA-preloaded striatum dissected from untreated and chronic nicotine-pretreated mice, indicating that repeated injections with nicotine did not alter the metabolism of [3H]DA taken up by the tissue. (-)-Quinpirole, a selective agonist for D2 DA receptors, and apomorphine, a nonselective D1/D2 agonist, inhibited the electrical stimulation-induced tritium efflux from striatum of untreated mice, whereas (+/-)-sulpiride, a D2 DA receptor antagonist, enhanced the evoked release of tritium. These changes in tritium efflux effected by (-)-quinpirole and (+/-)-sulpiride reflected changes in [3H]DA release and not in DA metabolism, as shown by separation of the released radioactivity on alumina columns. The D1 receptor agonist (+/-)-SKF-38393 did not affect the tritium overflow, whereas the D1 receptor antagonist (+)-SCH-23390 exerted a stimulatory action but only at a high concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The distribution of cathepsin D activity in adult and aging human brain regions.
We measured the activity of cathepsin D, the major cerebral protease, in 50 separate areas of the central nervous system of adult and aged humans, using hemoglobin as the substrate. The activity showed significant regional heterogeneity, with average differences of 50-100% between the lower and higher level areas, and a more than threefold difference between the lowest and highest levels. The forebrain, midbrain, and hindbrain each had areas of high and low activity; cerebellum and cord areas were among those with low activity. Cathepsin levels tended to increase with age in about half of the areas analyzed, and the increases were significant in 14. Statistically significant decreases with aging were observed in two areas. The increases varied between 30 and 60%, and the decreases were 20%. Enzyme activity in thalamus, hypothalamus, pons, medulla, and cerebellum increased with age. In the ventrolateral medulla, which contains the major portion of the cerebral noradrenergic cells, the cathepsin D levels increased with age; in the dorsal raphe area, which contains the major portion of the cerebral serotonergic cells, the enzyme levels decreased. The change with age in human brain seems to be less than what we observed in rat brain, where activity more than doubled in most areas. The changes in enzyme levels need to be tested at more ages to establish a pattern of changes in activity throughout life.
Adult↗
Changes in free amino acid concentrations in serum, brain, and CSF throughout embryogenesis.
Using the developing chick embryo as a model and a very sensitive micromethod for amino acid analysis, a complete analysis is presented of the developmental changes in free amino acid concentration in the blood, in the CSF, and in two different brain regions (optic lobe and frontal lobe) of the chick embryo (from day 4 of incubation, until day 5 post hatching). The developmental profile of Lys is the only one that is almost identical in all three compartments. The developmental profiles of the serum and of the brain are very similar for Arg and Phe, less so for Leu and Gly, and towards the end of the embryonic period, similar also for Val, Ile, Trp, and Met. The amino acid concentrations in the CSF are either much lower than in serum and brain already at the earliest stages, or they progressively decline to levels lower than those in brain and serum, most rapidly between day 6 and 8 of embryonic life. The concentrations of neuroactive amino acids (Gln, Glu, Asp, GABA, Tau, and Gly) in both brain regions begin to increase very early, and continue to rise, except Tau, which goes through a maximum at day 8. Comparative analysis of the developmental profiles of each amino acid in serum, brain, and CSF reveals that the blood supply and the cellular uptake, retention, and metabolism by neural cells are the major determinants of the free amino acid pool of the developing brain.
Amino Acids↗