Noradrenaline In Rat Brain Research Articles

Expression of aggression attenuates stress-induced increases in rat brain noradrenaline turnover

This experiment determined whether or not an aggressive biting response could attenuate stress-induced increases in brain noradrenaline (NA) turnover, by measuring contents of NA and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO 4), in discrete brain regions of male Wistar rats. Rats were exposed to a 10 min supine restraint stress with or without being allowed to bite a wooden stick. In each group, the animals were sacrificed by decapitation either 0 min or 50 min after release from stress. NA and MHPG-SO 4 levels were unaffected in both biting and non-biting groups immediately after stress, as compared to controls. Fifty min after release from stress, increases in plasma corticosterone levels induced by stress recovered in the biting group but remained high in the non-biting group. MHPG-SO 4 levels significantly increased in the hypothalamus, amygdala, thalamus, midbrain, basal ganglia, hippocampus and cerebral cortex in both stressed groups, however the increases in the non-biting group were significantly higher than those in the biting group in the first 5 of these regions. These findings clearly show that giving rats an opportunity to express aggression during stress exposure results in a significant attenuation of stress-induced increases in NA turnover in specific brain regions, such as the hypothalamus and limbic areas. The present experiment provides a possible neurochemical basis for clinical studies showing that suppression of anger in a stressful, frustrating situation leads to pathological consequences in humans.

Time course of changes in serotonin and noradrenaline in rat brain after predictable or unpredictable shock

The effects of predictable and unpredictable shock on concentrations of serotonin (5-hydroxytryptamine, 5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan (TP) and noradrenaline (NA) have been studied in 7 regions of rat brain. Two separate experiments have been carried out determining these substances both at 30 min and 2 h after the stress session. Unpredictable shock depleted NA levels in all brain regions except the striatum. However, at 2 h poststress NA in these regions increased significantly in comparison with both controls and predictably shocked rats. Predictable shock also decreased NA in locus coeruleus, brainstem and hypothalamus, which was not observed 2 h later. Both predictable and unpredictable shock decreased 5-HT in brainstem and hypothalamus. At 2 h poststress, 5-HT levels in these regions were still decreased in predictably shocked rats, but had attained control values in unpredictably shocked rats. 5-HT metabolism expressed as the 5-HIAA/5-HT ratio, was significantly increased 30 min after predictable shock in all regions except the locus coeruleus and hippocampus. Unpredictable shock produced a much more marked increase in 5-HIAA/5-HT ratio. At 2 h poststress 5-HT metabolism returned to control values in most of the brain regions of predictably shocked animals, but it remained high after unpredictable shock. The activation of serotonergic metabolism following each type of shock is different according to the nucleus in which the 5-HT nerve endings originate. Only slight increases in tryptophan were observed after both types of shock. Our results suggest that unpredictable shock is perceived as a more anxiogenic situation and that under this condition both 5-HT and NA levels are more effectively normalized with time.

Chronic Stress Increases Serotonin and Noradrenaline in Rat Brain and Sensitizes Their Responses to a Further Acute Stress

The effects of 1 h/day restraint in plastic tubes for 24 days on the levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan (TP), and noradrenaline (NA) in six regions of rat brain 20 h after the last restraint period were investigated. The levels of 5-HT, 5-HIAA, and NA but not TP increased in several regions. The effects of 1 h of immobilization on both control and chronically restrained rats were also studied. Immobilization per se did not alter brain 5-HT, 5-HIAA, and TP levels, but decreased NA in the pons plus medulla oblongata and hypothalamus. However, immobilization after chronic restraint decreased 5-HT, increased 5-HIAA, and decreased NA in most brain regions in comparison with values for the chronically restrained rats. We suggest that chronic restraint leads to compensatory increases of brain 5-HT and NA synthesis and sensitizes both monoaminergic systems to an additional acute stress. These changes may affect coping with stress demands.

O-168 - Expression of aggressive response attenuates stress-induced increases in regional rat brain noradrenaline turnover

O-168 - Expression of aggressive response attenuates stress-induced increases in regional rat brain noradrenaline turnover

Effect of urapidil on rat brain catecholamine synthesis.

The effects of urapidil, a clinically effective antihypertensive drug, on the in-vivo rate of synthesis of rat brain noradrenaline (NA) and dopamine (DA) was determined. A significant dose-dependent increase in dopa concentration by urapidil after dopa decarboxylase inhibition by NSD 1015 was observed in brain stem (3-30 mg kg-1 i.p.) and striatum (10-30 mg kg-1 i.p.), indicating increased NA and DA turnover, respectively, most probably a result of central blockade of brainstem alpha 1-adrenergic and striatal DA receptors. These results indicate that urapidil may possibly exert its central hypotensive action in part by a reduced influence on brain stem NA, thus reducing central sympathetic outflow.

Relation between brain monoamine oxidase (MAO) activity and the firing rate of locus coeruleus neurons.

Utilizing a specific "low substrate concentration technique", intrasynaptosomal MAO-A and MAO-B activities within the rat brain noradrenaline system were studied. It was found that mainly MAO-A was localized intrasynaptosomally, whereas MAO-B contributed with less than 15% of the total intrasynaptosomal MAO activity, a phenomenon that was also observed within the central dopamine system. It is suggested that the intrasynaptosomal pool of MAO in the noradrenaline and the dopamine systems may reflect the density of innervation of the respective system throughout the brain. In addition, the effects of various selective monoamine oxidase (MAO) inhibitors on the noradrenergic intrasynaptosomal MAO activity as well as on the neuronal firing rate of noradrenaline containing cells in the locus coeruleus (LC) were investigated. Pretreatment with the MAO-A selective inhibitors clorgyline (10 mg/kg, i.p., 1 h) or (+)-FLA 336 (1 mg/kg, i.p., 1 h) caused a significant depression (40%) of mean spontaneous firing rate of LC neurones, randomly encountered throughout the LC. The MAO-B selective inhibitor pargyline (10 mg/kg, i.p., 1 h) was found to lack effect in this regard. However, pretreatment with (-)-deprenyl (10 mg/kg, i.p., 1 h), equally a selective MAO-B inhibitor, markedly suppressed the spontaneous firing rate of LC units. This inhibition by (-)-deprenyl was blocked by pretreatment with SK&F 525 A (50 mg/kg, i.p., 30 min), an inhibitor of microsomal drug metabolizing enzymes. Thus, the depression of LC units by (-)-deprenyl seems to be executed by a metabolite, e.g. l-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of detomidine on the release and turnover of noradrenaline in rat brain.

The effect of detomidine, a novel veterinary sedative/analgesic, on the release and turnover of noradrenaline in rat brain was studied using both in vitro and in vivo techniques. Xylazine was included in the studies for comparison. Rat occipital cortex slices were preloaded with 3H-noradrenaline and the potassium-evoked release of tritium was measured using a superfusion system. Both detomidine and xylazine produced concentration dependent inhibition of stimulation evoked tritium release. A maximal inhibition of 66 and 50% was achieved at detomidine and xylazine concentrations of 1 X 10(-7) and 1 X 10(-6) M, respectively. The dose-response curve of detomidine was shifted to the right in a parallel manner by the selective alpha 2-antagonist idazoxan. Detomidine, while not altering the endogenous levels of noradrenaline, dopamine and 5-hydroxytryptamine, induced a dose-dependent inhibition of noradrenaline turnover as measured by the alpha-methyl-p-tyrosine method. Moreover, detomidine decreased the concentration of MHPG-SO4, the principal metabolite of central noradrenaline, in rat brain. Xylazine was in these tests at least two orders of magnitude less potent than detomidine.

Effects of neurotensin on regional concentrations of norepinephrine in rat brain

The effects of intraventricular administration of either 7.5 or 30 μg neurotensin on norepinephrine concentrations were examined in several brain regions at 5 or 30 min post-injection. Significant elevations in the level of this amine were found in the hypothalamus, nucleus accumbens and amygdala. Levels in striatum, ventral tegmentum, septum, frontal cortex and substantia nigra were not affected. The effects were most prominent 5 min after injection. Results are discussed in terms of behavioral changes induced by these doses of neurotensin.

新抗うつ薬，ＭＯ‐８２８２の薬理学的性質 ＩＩ

We investigated the pharmacological characteristics of MO-8282 as a novel antidepressant. MO-8282 inhibited the specific binding of 3H-clonidine to cerebro-cortical membrane fractions from rats about five times more potently than mianserin, and it competed with clonidine in the twitch response of the isolated guinea-pig ileum under field stimulation. The results indicated that MO-8282 possessed alpha 2-adrenergic receptor blocking activity. MO-8282 in a dose of 30 mg/kg (p.o.) showed no inhibition against the uptake of noradrenaline, dopamine and serotonin in the rat brain, whereas mianserin inhibited the uptake of serotonin specifically. MO-8282, similar to mianserin, had no effect on spontaneous release of 3H-noradrenaline and slightly stimulated the release of 3H-serotonin from the rat cerebrocortical synaptosome. The turnover rate of noradrenaline in rat brain was accelerated by administration of MO-8282 (30 mg/kg) for 15 days; however, that of dopamine and serotonin was not affected. The above findings indicate that MO-8282, unlike tricyclic antidepressants, mainly exerts alpha 2-adrenoceptor blocking action on the central noradrenergic system, similar to mianserin. In addition, the fact that MO-8282 unlike mianserin showed no inhibition against uptake of serotonin in brain suggests that the alpha 2-adrenoceptor blocking of MO-8282 is more specific and potent than that of mianserin.

The oxidation of adrenaline and noradrenaline by the two forms of monoamine oxidase from human and rat brain

The selective monoamine oxidase inhibitors clorgyline and (?)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (?)-noradrenaline and (+),(?)-adrenaline in homogenates from seven different regions of human brain. The activities towards 5-hydroxytryptamine and 2-phenethylamine, which are essentially specific substrates for the A- and B-forms, respectively, under the conditions used in this work, were also determined. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. The total MAO activity was found to be highest in the hypothalamus and lowest in the cerebellar cortex. Use of the selective MAO inhibitors clorgyline and (?)-deprenyl also showed adrenaline and noradrenaline to be substrates for both forms of the enzyme in rat brain. In human cerebral cortex and rat brain the two forms were found to have similar K(m)-values and maximum velocities towards adrenaline. These values for the two forms were also found to be similar in human cerebral cortex when noradrenaline was used as the substrate. In contrast MAO-A showed a significantly lower K(m) and a higher maximum velocity towards noradrenaline in rat brain. These results suggest that the rat may not provide a close model of the human for studies on the effects of MAO inhibitors on brain noradrenaline metabolism.

Effects of preshock experience on enhancement of rat brain noradrenaline turnover induced by psychological stress

The present study examined alterations of brain noradrenaline (NA) turnover as a function of preshock and psychological stress treatments, by measuring contents of NA metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO 4), in discrete brain regions of male Wistar rats. Psychological stress induced by exposing to the sight, sound and odor of other rats being shocked produced higher levels of MHPG-SO 4 in the hypothalamus, amygdala and locus coeruleus (LC) region, as well as higher levels of plasma corticosterone. Preshock experienced rats also showed marked increases of MHPG-SO 4 levels in the same regions described above and elevated plasma corticosterone levels when placed but not shocked in the same environment in which the rats had previously received shocks. The effects of psychological stress on brain NA turnover were affected by the animal's shock history preferentially in the hypothalamus and amygdala. These results suggest that: (1) a purely psychological stressor caused acutely enhanced NA turnover in specific brain regions; (2) regional NA activity appeared to be reinstated simply by reexposure to the environment previously associated with shock; (3) preshock experience further intensified the enhancement of amygdaloid NA turnover evoked by psychological stress. An additional expriment, studying the aftereffects of preshock experience, clearly showed that these findings result from sensitization or conditioning to the environment previously paired with shock, and not merely from the aftereffects of the shock per se.

Chronic treatment with the potential antidepressant drug rolipram: the effect on the behavioural responses to adrenergic and dopaminergic receptor agonists with some biochemical correlates.

We studied the effect of acute and chronic treatment with rolipram, a potential antidepressant drug, on the behavioural responses induced by adrenergic and dopaminergic receptor agonists in mice and rats, and on (3H)prazosin and (3H)dihydroalprenolol binding to cortical membranes and whole brain noradrenaline and dopamine utilization in rats. Chronic, but not acute, administration of rolipram potentiated a behavioural response mediated through central alpha 1-adrenoceptors, attenuated an alpha 2-adrenoceptor-mediated response and inhibited a beta-adrenoceptor-mediated response. Neither treatment affected the behavioural responses to dopaminergic stimulants. Repeated treatment with rolipram decreased the density of cortical (3H)dihydroalprenolol, but not (3H)prazosin bindings sites, and reduced brain noradrenaline, but not dopamine utilization. These results suggest that chronic administration of rolipram induces the down-regulation of the central beta- and alpha 2-adrenoceptors and enhances the responsiveness of the central alpha 1-adrenoceptors with no apparent changes in the alpha 1-adrenoceptor density.

Effects of amiflamine and related compounds on the accumulation of biogenic monoamines in rat brain slices in vitro and ex vivo in relation to their behavioural effects.

The inhibition of the accumulation of serotonin, noradrenaline and dopamine in rat brain (occipital cortex and striatum) slices by amiflamine and its two major metabolites FLA 788(+) and FLA 668(+) was examined and compared with that of amine releasing compounds e.g. p-chloroamphetamine (PCA) and alpha-ethyltryptamine and uptake inhibitors, e.g. alaproclate, citalopram, desipramine, fluoxetine and norzimeldine. It was found that amiflamine and FLA 788(+) inhibited the accumulation of serotonin and noradrenaline but only slightly that of dopamine in vitro and ex vivo with a mechanism similar to that of PCA and alpha-ethyltryptamine, i.e. with higher potency in reserpinized rats than in normal animals suggesting amine releasing mechanisms. Similar to alpha-ethyltryptamine and PCA, amiflamine and FLA 788(+) caused behavioural changes (serotonin syndrome) which were particularly pronounced in reserpinized rats but also observed after a second administration of amiflamine in normal rats. Upon repeated administration of amiflamine the behavioural changes disappeared which indicates a functional down-regulation of the serotonin receptors responsible for this syndrome. FLA 668(+) inhibited the accumulation of noradrenaline in vitro and ex vivo but had less effect on the accumulation of dopamine and particularly that of serotonin. It is concluded that amiflamine and FLA 788(+) inhibit the accumulation of serotonin and noradrenaline by releasing mechanisms and that the released serotonin triggers the behavioural changes observed.

Pharmacology in vivo of the phenylindan derivative, lu 19-005, a new potent inhibitor of dopamine, noradrenaline and 5-hydroxytryptamine uptake in rat brain

Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCI], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios. Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and alpha-methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range. The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA- and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT- and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models.(ABSTRACT TRUNCATED AT 250 WORDS)

The differential observation of type A and B MAO-containing terminal fibers in the cerebral cortex of the rat

The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. The activities towards 5-hydroxytryptamine and 2-phenethylamine, which are essentially specific substrates for the A- and B-forms, respectively, under the conditions used in this work, were also determined. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. The total MAO activity was found to be highest in the hypothalamus and lowest in the cerebellar cortex. Use of the selective MAO inhibitors clorgyline and (−)-deprenyl also showed adrenaline and noradrenaline to be substrates for both forms of the enzyme in rat brain. In human cerebral cortex and rat brain the two forms were found to have similar Km-values and maximum velocities towards adrenaline. These values for the two forms were also found to be similar in human cerebral cortex when noradrenaline was used as the substrate. In contrast MAO-A showed a significantly lower Km and a higher maximum velocity towards noradrenaline in rat brain. These results suggest that the rat may not provide a close model of the human for studies on the effects of MAO inhibitors on brain noradrenaline metabolism.

O4C1536) - Effects of coping with stress on rat brain noradrenaline turnover depend on the complexity of coping task.

O4C1536) - Effects of coping with stress on rat brain noradrenaline turnover depend on the complexity of coping task.

Effect of a new eburnamine derivative, RU 24722, on the turnover of monoamines in mouse brain: Selective and reversible decrease of noradrenaline

A new eburnamine derivative, is RU 24722, structurally similar to vincamine and is known to cause a specific and reversible decrease of noradrenaline in rat brain. The effects of RU 24722 on the turnover of monoamines in mouse brain were investigated. The noradrenaline level in mouse brain was significantly decreased after administration of RU 244722 10 mg/kg i.p. with significant increases in 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid. The levels of these compounds returned to the control levels within 5 h. The levels of d dopamine, serotonin, 5-hydroxyindoleacetic acid and histamine were not affected by this dose of RU 24722. Higher doses of RU 24722 (25 and 50 mg/kg) decreased the concentration of serotinin significantly with a significant increase in 5-hydroxyindoleacetic acid. There were no differences between the patterns of changes in the forebrain, midbrain and hindbrain. These results indicate that RU 24722 increased the turnover of noradrenaline and dopamine i in mouse brain at the dose of 10 mg/kg and the turnover of serotonin was also increased only at higher doses.

P-4) - The role of brain noradrenaline in rats during coping with stress

P-4) - The role of brain noradrenaline in rats during coping with stress

Effects of CGP 11305 A, a new reversible and selective inhibitor of MAO A, on biogenic amine levels and metabolism in the rat brain.

CGP 11305 A [4-(5-methoxy-7-bromo-benzofuranyl-2)piperidine HCl), a reversible, selective inhibitor of MAO A, increased the levels of rat brain noradrenaline, dopamine, and serotonin dose-dependently and to approximately the same extent. Concomitantly, it lowered the levels of their metabolites, MHPG-SO4, HVA, DOPAC, and 5-HIAA. When compared with the irreversible MAO A inhibitor clorgyline, the effects of CGP 11305 A were of much shorter duration. Moreover, the increases of noradrenaline and serotonin and the decreases of their metabolites MHPG-SO4 and 5-HIAA were smaller after CGP 11305 A than after clorgyline in equieffective doses for MAO A inhibition. CGP 11305 A decreased the synthesis of catecholamines and serotonin less markedly than clorgyline. This is probably due to the reversibility of the interaction of the compound with MAO A. In contrast to CGP 11305 A, clorgyline increased the level of dopamine less than those of noradrenaline and serotonin. This is explained by assuming that dopamine synthesis is particularly sensitive to end product inhibition. CGP 11305 A also exhibited some inhibitory properties on the uptake of serotonin and, to a lesser degree, of noradrenaline in vitro and in vivo. Compared with MAO inhibition, however, uptake inhibition required 30-100 times higher doses.

Development of receptors for dopamine and noradrenaline in rat brain

In order to examine the receptor basis for the development of spontaneous locomotion and for the effects of clonidine in the infant rat, we measured the densities of α 1-adrenoceptors, α 2-adrenoceptors and D 2-dopamine receptors in various brain regions of the developing infant Wistar rat. The mesolimbic D 2-dopamine receptors paralleled the rise in spontaneous locomotion of the infant rat. No α 1-adrenoceptors were detectable at birth in any of the four regions examined (mesolimbic, hippocampus, frontal cortex, and hypothalamus), thus providing no basis for the locomotor-stimulating action of clonidine in the first week of life. Mesolimbic α 2-adrenoceptors matured between 21 and 28 days (at which time clonidine yields its usual sedating action).