Disturbances in catecholamine metabolism during formation and development of chronic alcoholism]

There has been carried out an investigation dealing with catecholamines metabolism in the patients suffering from alcoholism in the first, second and third stage at the short-term remission. The first developed alcoholism stage was determined as a typical one for increasing the excretion with urine of DOPA, dopamine (DA), noradrenaline (NA) and adrenaline (A), as well as the blood levels of DA, NA and A. DA/NA rate evidences about an increased synthesis of NA with DA. The marked second alcoholism stage is characterized by an acute decrease of excreting with urine and blood levels of NA. Alongside with the latter. DA excretion with urine and its blood levels remained high. DA/NA rate indicates to the considerably low relative activity of NA with DA synthesis, both in relation to the control and to the developed first alcoholism stage. In the third alcoholism stage NA excretion with urine and its blood levels become lower relatively to the marked second stage. Simultaneously DA excretion with urine and its blood levels are lower than in the developed second stage, hower exceed the control values. DA/NA rate testifies the slight activation of NA and DA synthesis. The results obtained in the work indicate to the significant role of CA metabolism disturbances in the alcoholic dependence formation.     

Dopamine-beta-hydroxylase inhibition acutely stimulates rats hypothalamic noradrenaline and dopamine neuronal activity as assessed from metabolic ratios and circulating glucose and ACTH responses

Because central noradrenaline neuronal activity is tonically inhibited by noradrenaline (NA) itself via an action at prejunctional alpha 2-adrenoceptors, it was hypothesised that the blockade of central NA synthesis following acute dopamine-beta -hydroxylase (DBH) inhibition might primarily deplete prejunctional NA levels and result in an increase in central NA neuronal activity through reduced NA autoinhibition. This hypothesis was tested in the rat following the acute administration of the DBH inhibitors diethyldithiocarbamate (DDC) and cysteamine (CSH). Computerised gas chromatography/mass spectrometry was used to precisely measure the hypothalamic levels of NA and dopamine (DA) together with those of their primary neuronal metabolites dihydroxyphenylethyleneglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC), respectively. Both DDC (at 4 h) and CSH (at 30 min.) caused approximately a 50% reduction of hypothalamic NA concentrations. However this was associated with marked and highly significant increases in hypothalamic DHPG levels (by 50-100%) and in the hypothalamic ratio DHPG/NA. Also, when measured after CSH, the hypothalamic levels of the DHPG metabolite 3-methoxy-4-hydroxyphenylethyleneglycol were highly significantly increased. Consistent with increased DA neuronal activity, both DBH inhibitors raised DA and DOPAC levels and also the ratio DOPAC/DA in the hypothalami of treated rats and markedly suppressed serum prolactin levels (all p less than 0.01). The rise in hypothalamic concentrations of DHPG indicates that an increase in hypothalamic NA neuronal activity occurs following DBH inhibition. Significant elevations of blood glucose, corticosterone and ACTH were also observed after DBH inhibition. As we have previously demonstrated that increased central NA activity is associated with elevations of blood glucose, corticosterone and ACTH, these data provide further evidence for a functional increase in central NA activity caused by acute DBH inhibition. It is proposed that the increase in hypothalamic NA activity after DBH inhibition results from a primary depletion of the prejunctional alpha 2-active autoregulatory pool of NA.     

Differential effects of experimentally induced blood pressure changes on the release of catecholamines in hypothalamic and limbic areas of rats

The effects of longer lasting blood pressure changes on the release of endogenous catecholamines (CA) in limbic and hypothalamic areas were studied in anaesthetized rats. For this purpose the central nucleus of the amygdala (AC), ventral hippocampus (VH) and medial hypothalamus (MH) were simultaneously superfused through push-pull cannulae with artificial cerebrospinal fluid and the release of the endogenous catecholamines dopamine (DA), noradrenaline (NA) and adrenaline (A) was determined before and after blood pressure manipulations. A fall in blood pressure elicited by the ganglionic blocking agent chlorisondamine resulted in different changes of the various CA release patterns in AC. Short lasting increased CA release rates as compared to prehypotension levels could be observed in the hippocampus. The activity of catecholaminergic neurons in MH remained unchanged. A rise in arterial blood pressure induced by intravenous injection of tramazoline did not change the release rates of DA in all 3 brain areas studied. In hippocampus, NA levels in the superfusates decreased initially during hypertension but returned to normal values 40 min after drug injection. In the late phase of hypertension increased rates of release of NA in the amygdala and of A in the hypothalamus could be observed. The different patterns in the release of CA suggest that DA, NA and A are differentially implicated in the regulation of experimentally induced blood pressure changes.     

Adrenocortical and thyroid systems of rats at the initial stage of nociceptive influence

There are two phases in the initial period of formation of adrenocortical response to sharp nociceptive influence. The first phase (within 10-15 sec.) involves emergency mobilization of "basal" reserves of hormone active substances. It is characterized by reduction of corticoliberine activity in hypothalamic and extrahypothalamic structures of the rat brain with a parallel increase of corticotrophin concentration in plasma, devastation of corticosteroid reserves in adrenal glands; a decrease in the level of corticosteroids in blood against the background of accumulating hormone in bodies-targets. In the second phace: the phase of hypercompensation, the progressive increase of credit of the substances under study was quite obvious. The authentic changes in a level of aldosterone in adrenal glands and blood took place only in 2.5 minutes after the stress. The nociceptive influence was also biphasic when acting upon the reorganization of thyroid status number. However, unlike the initial adrenocortical response to stress in the first phase of thyroid reaction, the elevation of plasma thyroxine and tri-iodothyronine level was obvious. At the second stage, selective decrease in concentration of thyroxine to normal amounts occurred.     

EFFECTS OF DEXAMETHASONE AND NERVE GROWTH FACTOR ON PHENYLETHANOLAMINE N-METHYLTRANSFERASE AND ADRENALINE IN ORGAN CULTURES OF NEWBORN RAT SUPERIOR CERVICAL GANGLION

Abstract— Phenylethanolamine N -methyltransferase (PNMT) and adrenaline (A) have been studied in organ cultures of neonatal rat sympathetic ganglia. Organ culture for 2 days without added nerve growth factor (NGF) caused a fall in noradrenaline (NA) and PNMT contents but there was no change in dopamine (DA) or A contents compared to controls. However, in the presence of dexamethasone, there was a marked increase in both PNMT activity and A content, but no change in NA or DA content. Addition of NGF to cultures stimulated with dexamethasone caused no further significant change in PNMT activity or A content, whereas both NA and DA were increased. Prolonged culture without NGF, in the presence of dexamethasone resulted in reductions in both NA and DA content, but the high levels of PNMT activity and A content were sustained. The results are consistent with the hypothesis that both PNMT and A are not contained in the noradrenergic cell bodies but are located chiefly within the small intensely fluorescent cells in sympathetic ganglia.     

Changes in the oxygen-dependent metabolic activity of polymorphonuclear leukocytes from the peripheral blood and macrophages from the peritoneal exudate in the experimental infection of mice with the causative agent of plague

The subcutaneous infection of C57BL/6J mice and noninbred white mice with 40 LD100 of Y. pestis virulent strain has been found to produce synchronous changes in the oxygen-dependent metabolism (ODM) of peripheral blood neutrophils in the spontaneous or zymosan-, E. coli- and Y. pestis-stimulated variants of the NBT test. These changes can be divided into three phases: (I) the phase of a sharp drop in ODM activity; (II) the phase of the increase of this activity, occurring simultaneously with the penetration of Y. pestis cells into the blood stream; and (III) the phase of the terminal decrease of ODM activity as the cytotoxic lesion of phagocytic cells occurs. Peritoneal exudate macrophages show a more gradual decrease in ODM activity. The infection of the animals with 40,000 LD100 of Y. pestis has been found to produce an increase in the ODM activity of neutrophils, rapidly followed by its decrease to the zero level. Macrophages show phasic changes in their ODM activity, identical to changes in the ODM values of neutrophils in mice infected with 40 LD100 of Y. pestis.     

Reproduction of electrographic correlates of a conditioned reflex after changes in the activity of the noradrenergic and dopaminergic systems

On the model of shortly delayed defensive conditioned reflex in cats, it was shown in acute experiments that pharmacologically elicited change of NA system activity (clonidine, 0.2 and 1.5 mg/kg intravenously) and of DA system activity (apomorphine, 3 mg/kg intravenously) leads to a definite manifestation of electrographic correlates of memory trace, i.e. of conditioned evoked potential (EP) in examined brain structures, as well as of conditioned neurographic response (CNR) and conditioned skin-galvanic reaction (SGR). The increase of the NA system activity causes a rise of the number of conditioned EPs in the reticular formation, hippocampus and preoptic area along with an enhancement of CNR reproduction. The increase of the DA system activity contributes to the appearance of conditioned EPs in the hippocampus, amygdalar complex and central gray matter, together with an enhancement of the reproduction of conditioned SGR.     

Post-mortem changes of neurotransmitter concentrations in the rat brain regions

Using High Performance Liquid Chromatography coupled with electrochemical detection the post-mortem stability of noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxy indole acetic acid (5-HIAA) were examined in the rat hypothalamus, amygdala, cerebral cortex, cerebellum and corpus striatum over an 8 hour time period. Changes in concentrations of the different neurotransmitters were less than it might be expected. The significant changes were: a. A fall in NA levels in the cerebral cortex by 4 hours and in the hypothalamus at 8 hours. b. A reduction in DA concentrations in the corpus striatum at 8 hours but a two fold rise of levels in the hypothalamus at 1 and 2 hours. c. A four-fold increase in 5-HT concentrations in the amygdala throughout the 8 hours studied. The results indicate that for comparative studies on post-mortem brain tissue correction factors should be employed to take into account differential changes in the concentrations of the various neurotransmitters.     

Glutathione system of erythrocyte and plasma in peptic ulcer

A complex study of the blood glutathione system has been carried out for the first time in patients with peptic (gastric and duodenal) ulcer. In erythrocytes and blood plasma of patients with the complicated peptic ulcer and postgastroresection syndromes there was the increase of conjugated dienes (and in the second group the increase in antioxidant activity). Under these conditions the main change was the sharp and identical decrease in glutathione peroxidase activity. In patients with uncomplicated peptic ulcer there was sharp increase in erythrocite and plasma glutathione reductase activity and plasma GSH. In operated but basically healthy patients plasma glutathione peroxidase remained decreased but plasma GSH sharply increased. Evidently complicated peptic ulcer is characterized by decreased functioning of the glutathione system. Activation of this system and the decrease or disappearance of manifestations of oxidative stress are associated with a favorable course of this disease, especially at uncomplicated peptic ulcer. The revealed changes significantly differ from those observed in patients with viral hepatitis, blle excretory diseases and strokes.     

The neurochemical mechanisms of the formation and consolidation of haloperidol-induced catalepsy

In rat brain cortex, haloperidol initiates the long-term potentiation of K(+)-induced Ca(2+)-dependent noradrenaline (NA) and dopamine (DA) secretion in vitro and in vivo. In both cases, the long-term potentiation is caused by the long-term increase in catecholamine content in the NA and DA terminals, as it has been shown in cortical tangential slices. Acute intraperitoneal haloperidol injection (2.5 mg/kg) evokes catalepsy and increases the content of NA and DA in the brain structures with localization of catecholamine receptors on terminals. This increase appears to be caused, predominantly, by modification of the terminal DA receptors, since only a trend to catecholamine increase is observed in the brain structures with a mixed type of NA and DA receptor localization (on somata and terminals). It is suggested that the long-term and diffuse action of haloperidol after its acute administration consists in the anxiogenic reaction and consolidation of catalepsy without an additional procedure of training and in the absence of unconditioned stimulus.     

Peripheral and central mechanisms of the pressor response elicited by stimulation of the locus coeruleus in the rat

Electrical stimulation of the pontine nucleus locus coeruleus (LC) caused an increase of the arterial blood pressure in anesthetized rats, and elevated plasma noradrenaline (NA) and adrenaline (A) levels. The stimulation-induced pressor response was characteristically biphasic and consisted of a sharp rise in arterial pressure at the onset of the stimulation, followed by a second elevation at the end of the stimulus. Bilateral adrenalectomy or adrenal demedullation completely blocked the secondary phase of the pressor response elicited by stimulation, but did not affect the primary phase. The latter was specifically eliminated by the destruction of the peripheral sympathetic vasomotor axons with intravenous 6-hydroxydopamine (6-OHDA). The active sites eliciting the secondary adrenomedullary pressor component appeared to be restricted to the nucleus LC, whereas the primary sympathetic vasomotor response could be elicited from sites in and around the nucleus. After brain transection at the midbrain level, stimulation of LC failed to evoke the adrenomedullary pressor response, while the sympathetic vasomotor component was not affected. Similarly, destruction of brain NA neurons by intraventricular administration of 6-OHDA did not change the sympathetic vasomotor response, but virtually abolished the adrenal response. The results demonstrate that the pressor response to stimulation of LC in the rat is due to both increased sympathetic vasomotor activity and CA released from the adrenal medulla. The study also provides evidence suggesting that the noradrenergic LC cell group play an important role in the activation of the adrenal medulla, but is not essential for the activation of the sympathetic vasoconstrictor fiber system.     

Effects of chlorpromazine on hypothalamic aminergic neurons and stress responses in moderate cold

Guinea-pigs were treated with chlorpromazine or 0.9% NaCl and exposed to +4 degrees C or +23 degrees C for 2 h. Hypothalamic noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), 3-methoxy-4-hydroxyphenylethylene-glycol (MHPG), homovanillinic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were determined by high-performance liquid chromatography. Serum and urinary catecholamines, muscle and liver glycogen and blood glucose were also measured. Chlorpromazine caused deep hypothermia at this moderately cold temperature and slight hypothermia at room temperature. Cold increased the activity of noradrenergic and serotonergic neurons, as indicated by the increase in hypothalamic MHPG and 5-HIAA and also the MHPG:NA and 5-HIAA:5-HT ratios. A tendency towards drug-induced inhibition of hypothalamic serotonergic neurons was seen, although this was not significant. A drug-induced inhibition of noradrenergic neurons could not be ruled out. Increased drug-induced turnover of DA was observed in the cold, and a tendency in the same direction was seen at room temperature. Excretion of DA into the urine was induced by chlorpromazine. The hypothermic guinea-pigs had low serum catecholamines, indicating diminished sympathetic activity, but high urinary catechols, a sign of cold stress.     

Contribution of Noradrenergic Neurons to the Regulation of Dopaminergic (D1) Receptor Denervation Supersensitivity in Rat Prefrontal Cortex

3,4-Dihydroxyphenylethylamine (DA, dopamine) levels in the rat prefrontal cortex were selectively decreased by 52%, leaving noradrenaline (NA) levels unaffected, 4 weeks following restricted bilateral electrolytic lesions of the ventral mesencephalic tegmentum (VMT). These lesions also induced a significant increase in DA-sensitive, but not isoproterenol-sensitive, adenylate cyclase activity in tissue homogenates (+38%). We had shown previously that chemical (6-hydroxydopamine, 6-OHDA) lesions of the VMT destroy both ascending DA and NA fibers but do not alter the D1-receptor density in the prefrontal cortex. In this study, electrolytic lesions of the VMT were combined with bilateral injections of 6-OHDA made laterally in the pedunculus cerebellaris superior to assess the role of NA fibers in the development of D1-receptor supersensitivity. This combined treatment produces a large decrease of cortical NA levels (-95%), an increase in beta-adrenergic-sensitive adenylate cyclase activity (+110%), and a decrease in DA levels (-60%), but does not alter D1-receptor density in the prefrontal cortex. These results indicate that the development of D1-receptor supersensitivity in the prefrontal cortex following electrolytic lesion of the VMT depends on the presence of an intact NA innervation.     

Catecholamine content (as measured by the HPLC method) in brain and blood plasma of the eel: effects of 101 ATA hydrostatic pressure

The catecholamine content (noradrenaline, NA; adrenaline, A; dopamine, DA, and its metabolite, DOPAC) was measured, by the HPLC method, in brain and blood plasma of eels studied at atmospheric pressure (1 ATA) or at 101 ATA of hydrostatic pressure (HP). In the brain, HP induces a slight but significant increase (P less than 0.05) in A and DA contents but NA and DOPAC levels are not modified at 101 ATA when compared to 1 ATA. In the plasma, only A and NA are detected, adrenaline being the predominant amine. In eels exposed to 101 ATA HP, A and NA are strongly increased (+100%; P less than 0.01). The significance of the catecholamine increase in brain and plasma of the eels under HP is discussed.     

Leukocytic shifts following pancreatic resection with a plasma scalpel and cryodestruction]

Two series of experiments were carried out on dogs. In the first series, blood leukocytes count was studied after resection of the pancreas using plasma scalpel. The resection caused two-phase leukocyte reaction: neutrocytosis (phase I) and leukocytosis involving mainly lymphocytes and monocytes (phase II). During the first 24 hours after the resection, a sharp increase of the leukocyte intoxication index (LII) was observed. The second series of experiments was performed using the combination of plasma scalpel and cryodestruction. The graphic curves denoted a sharp fall both in total leukocytic counts and in the different types of leukocytes which were plotted separately (neutrophils, eosinophils, etc.) This can be explained by the absence of the second (lympho-monocyte) reaction. Only a slight increase in LII occurred. These results reflect lower degree of the protection and adaptation reactions of leukocytes, this being in favor of a combination of plasma scalpel and cryodestruction during the operation.     

Role of monoamine oxidase-B in medroxyprogesterone acetate (17-acetoxy-6 alpha-methyl-4-pregnene-3, 20-dione) induced changes in brain dopamine levels of rats

The effect of medroxyprogesterone acetate (MPA) on brain monoamine levels and monoamine oxidase (MAO) activity was studied in adult, healthy, non-pregnant female rats. MpA was injected in a single dose of 100 mg/kg i.m. Dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT) levels and MAO activity were estimated fluorometrically in rat brian. No change in DA, NA, 5-HT or MAO activity was observed after 7 days of MPA treatment while a significant decrease in DA levels along with a significant increase in MAO activity was observed after 21 days of MPA treatment. However, there was no change in NA and 5-HT levels after 21 days of MPA administration. The selective reduction of DA by MPA could be due to an increase in MAO-B activity. MPA does not appear to increase MAO-A activity because neither of the specific substrates (NA and 5-HT) of MAO-A was found to be decreased inspite of the increase in MAO activity as estimated by the kynuramine method. These findings suggest the importance of MAO-B also in DA metabolism in rat brain.     

Brain and plasma biogenic amines analysis by the EC-HPLC technique: application to fish

A HPLC technique has been developed for the analysis of biogenic amines (noradrenaline, NA; dopamine, DA; adrenaline, A; serotonin, 5-HT) in tissues and blood and then applied to fish. It appears that when compared to classical methods, HPLC is more rapid and reliable with a lower variation in the results. This technique showed that in eel blood, 5-HT and DA (and their metabolites) are missing or at least are present at very low concentrations.     

Plasma leptin concentrations in phenylketonuric patients

High levels of phenylalanine (Phe) in blood have been shown to reduce dopamine (DA) and noradrenaline (NA) production. Leptin levels rise with increasing adiposity in rodents and humans acting as a negative feedback adipostatic signal to brain centers. The aim of this study was to evaluate leptin plasma levels in phenylketonuria (PKU) patients adhering to their special diet and in those on a 'loose diet'. Forty-nine patients with classical PKU were divided into two groups. Those in group A (n = 21) adhered very strictly to their diet (Phe: 0.15 +/- 0.04 mmol/l) and those in group B (n = 28) were on a 'loose diet' (Phe: 0.8 +/- 0.04 mmol/l). Thirty healthy children of comparable age served as controls. Both patients and controls were in pubertal stage 0 (Tanner). BMI (kg/m(2)) was evaluated in all the members of the groups. Their daily nutrients were calculated with a 7-day dietary protocol. Leptin was evaluated by RIA, and Phe and Tyrosine with an amino acid autoanalyser. Adrenaline (A), NA and DA were measured by an HPLC method. Plasma leptin in group B patients (28.4 +/- 2.0 ng/ml) was significantly increased as compared to group A patients (16.8 +/- 2. 6 ng/ml) and controls (17.8 +/- 3.0 ng/ml; p < 0.001). Plasma DA, A, and NA in group B was lower than in group A and controls. Additionally, leptin negatively correlated with A and DA, whereas Phe positively correlated with the hormone in all groups. Leptin, also, correlated with BMI only in group A and controls. Additionally, the hormone negatively correlated with the total energy intake only in group A (r = -0.43, p < 0.01) and in controls (r = -0.040, p < 0.01). It is suggested that the disregulation of the neuroendocrine system as well as the high Phe blood levels might play an important role in the increased leptin concentrations in PKU patients on a 'loose diet'.