Norepinephrine In Cerebral Cortex Research Articles

Evidences for amelioration of reserpine-induced fibromyalgia in rat by low dose of gamma irradiation and duloxetine

Objective: Fibromyalgia is a prevalent disorder characterized by chronic widespread pain and complex symptoms. This study was conducted to investigate the potential therapeutic effect of low-dose irradiation (LDI) alone or in combination with duloxetine on the reserpine-induced fibromyalgia in rats.Methods: Fibromyalgia was induced by administration of reserpine (1 mg/kg/s.c) for 3 consecutive days. Duloxetine (30 mg/kg, p.o) was administered 60 min before a forced swimming test (FST), and rats were exposed to a single dose of γ-radiation (0.5 Gy) 1 day before the FST.Results: Reserpine significantly increased immobility time in the FST, decreased the amount of 5-hydroxytryptamine, dopamine, and norepinephrine in cerebral cortex. It also increased malondialdehyde and nitric oxide and reduced glutathione contents in brain tissue. LDI alone or combined with duloxetine completely antagonized reserpine-induced fibromyalgia as assessed by the measured parameters. One of the most significant findings in this study was that the therapeutic effect of duloxetine was more pronounced by its combination with LDI. A possible mechanism of action of LDI and duloxetine responsible for their therapeutic effect was discussed.Conclusion: On the basis of the presented evidences, it could be concluded that LDI alone or combined with duloxetine could be of value in the management of fibromyalgia.

Effects of noradrenergic lesions on the development of rolipram-sensitive, low- Km, cyclic AMP specific phosphodiesterase in rat brain

Rolipram-sensitive, low- K m, cyclic AMP specific phosphodiesterase (PDE4) belongs to a superfamily of phosphodiesterases that hydrolyzes cyclic nucleotides. Ample evidence suggest that PDE4 is regulated by β-adrenergic receptors both in cultured cells and in adult rat brain. The present study investigated the effects of neonatal noradrenergic lesions on PDE4 in developing rat brain in comparison to that in the adult rats. Neonatal 6-hydroxydopamine treatment produced selective noradrenergic lesions (>80% loss of norepinephrine in cerebral cortex) without affecting dopaminergic systems. The lesions resulted in temporary reduction of PDE4 activity in cerebral cortex, cerebellum and brainstem. Lesions in the adult rats, on the other hand, did not alter PDE4 activity. Decreased PDE4 activity by neonatal noradrenergic lesions was due to a decrease in the V max of cAMP hydrolysis by PDE4, and not a change in the K m values. Immunoblot analysis showed that decreased PDE4 activity in cerebellum was associated with reduced expression of PDE4A5, PDE4A1, and several PDE4B variants. No change in the expression of any PDE4 subtype in cerebral cortex was detected with the antibodies used in this study. Neither the permanent loss of noradrenergic innervation in cerebral cortex, nor the permanent noradrenergic hyperinnervation in brainstem was accompanied by any permanent change in PDE4 activity. Decreasing PDE4 activity early after neonatal noradrenergic lesions might be important in maintaining constant concentrations of cAMP, which is critical for the cellular proliferation and differentiation that is active during this period.

A small subset of cortical astrocytes in culture accumulates glycogen

We are interested in identifying the target cells for norepinephrine in cerebral cortex and in characterizing the effects of norepinephrine on these target cells. Norepinephrine inhibits the incorporation of tritiated glucose into glycogen in rat cerebral cortex in dissociated cell culture. To identify which cells store glycogen in these cultures we combined glycogen cytochemistry with glial flbrillary acidic protein immunocytochemistry. Using this technique we show that cytochemically detectable glycogen is restricted to a small subset of astrocytes as well as an unidentified cell type which does not contain glial fibrillary acidic protein.These results demonstrate that only a minority of astrocytes in cortical cultures accumulate glycogen. Therefore cortical astrocytes are differentiated with respect to glycogen accumulation, an important metabolic function. We do not know if glycogen accumulation in astrocytes is a constitutive or facultative property. In either case the subset of astrocytes which accumulates glycogen might be one of the major cellular targets for norepinephrine in cerebral cortex.

Effect of MPTP and its pyridinium metabolites on monoamine uptake and on central catecholamine neurons in mice.

The effect of MPTP and its pyridinium metabolites MPDP+ and MPP+ on the in vitro [3H]monoamine uptake in synaptosomal preparations from mouse striatum and cerebral cortex was investigated. All compounds inhibited [3H]monoamine uptake in a dose-dependent manner in both regions analysed. MPP+ had the highest affinity to dopamine and noradrenaline uptake sites, while MPTP had the highest affinity to serotonin uptake sites. The results indicate that the affinity of MPP+ to different monoamine uptake sites appears to be better correlated to MPTP neurotoxicity as expressed in vivo than MPTP and MPDP+. Intracerebral injection of MPP+ into substantia nigra produced an almost complete disappearance of dopamine in striatum and noradrenaline in cerebral cortex, while injection of MPTP or MPDP+ had no or only moderate catecholamine-depleting effects. The MPP+-induced catecholamine depletion could be partially reversed by pretreatment with the catecholamine uptake blocker nomifensine. Histological analysis disclosed that MPP+ was a potent generally cytotoxic agent, while MPDP+ less and MPTP least so. The present results are compatible with the view that an interaction with the catecholamine uptake mechanism, probably through an uptake and accumulation of extraneuronally formed MPP+, is most likely the explanation for neuron-specific neurotoxic action on catecholamine neurons following MPTP administration.

Neuronal responses to noradrenaline in the cerebral cortex: evidence against the involvement of alpha 2-adrenoceptors.

The technique of microelectrophoresis was used to test the hypothesis that alpha 2-adrenoceptors are involved in mediating the excitatory responses of single neurones to noradrenaline in the somatosensory cerebral cortex of the rat. In the first series of experiments the effects of two alpha 2-adrenoceptor antagonists, yohimbine and idazoxan (RX-781094), were compared on excitatory responses to noradrenaline, phenylephrine and acetylcholine. The response to noradrenaline was not more susceptible to antagonism by these drugs than the response to the alpha 1-adrenoceptor stimulant, phenylephrine. Yohimbine antagonized responses to all three agonists equally, while idazoxan antagonized responses to noradrenaline and phenylephrine equally with relative preservation of responses to acetylcholine. In the second series of experiments the effects of the selective alpha 2-adrenoceptor stimulant, UK-14304, were examined. UK-14304 produced weak and inconsistent excitations on a small number of cells; however, most of the cells did not respond to this drug. When applied continuously using low ejection currents, UK-14304 selectively and reversibly antagonized responses to noradrenaline and phenylephrine without affecting responses to acetylcholine. These results suggest that, in the somatosensory cortex of the rat, neuronal excitation to noradrenaline is unlikely to be mediated either wholly or partly by alpha 2-adrenoceptors. The antagonism of neuronal responses to noradrenaline and phenylephrine by idazoxan probably reflects the alpha 1-adrenoceptor antagonistic properties of the drug which is known to occur at higher concentrations. The low agonistic potency of UK-14304 and the antagonism of responses to noradrenaline and phenylephrine by UK-14304 suggest that this drug, like clonidine, may act as a partial agonist at alpha-adrenoceptors.

Correlations Histopathologiques et Neurochimiques en Fonction de Lesions de la Regiondu Locus Coeruleus chez le Chat (Part I)

Unilateral lesions in the area of the loci coeruleus and subcoeruleus in the cat are associated with a significant and sustained decrease of noradrenaline (NA) in the ipsilateral cerebral cortex without any important change in the concentrations of NA in the contralateral cortex and in the spinal cord of both sides. The serotonin (5-HT) concentrations of the spinal cord and cerebral cortex of both sides remained unchanged in the same groups of animals. Bilateral lesions in the same area result also in a marked decrease of NA in the cerebral cortex of both sides. The latter lesions also result in slight decreases of NA in the hypothalamus and of NA and 5-HT in the spinal cord but the NA and 5-HT concentrations of the striatum and thalamus and the 5-HT concentrations of the cerebral cortex and hypothalamus are unmodified by such lesions. Unilateral lesions of the area immediately rostral to the locus coeruleus (praelocus lesions) result in a very significant decrease of NA in the ipsilateral cerebral cortex without any change of NA in the contralateral cerebral cortex and spinal cord of both sides. Similar lesions produced bilaterally in another group of cats resulted in marked decreases of NA in the cerebral cortex of both sides and a slight decrease of NA in the thalamus without any change of NA in the striatum, hypothalamus and spinal cord and of 5-HT in the cerebral cortex. In the same group of animals with lesions which, however, extended more closely to the midline than in cats with locus coeruleus lesions, 5-HT is markedly decreased in the striatum and thalamus and slightly decreased in the hypothalamus and spinal cord. These results support the view that the noradrenergic coeruleo-cortical pathway is made up of fibers which originate in the loci coeruleus and subcoeruleus and predominantly end ipsilaterally to their origin in the cerebral cortex. Ascending NA fibers ending in the thalamus appear to originate from NA neurons located more laterally in the upper pons and more specifically at the level of the parabrachial nuclei.

Uptake and release of noradrenaline in rat cerebral cortex in vitro: No effect of benzodiazepines and barbiturates

The effects of two barbiturates (phenobarbitone and pentobarbitone) and one benzodiazepine (chlordiazepoxide) were studied on uptake, retention and spontaneous and stimulation-induced release of 3H-noradrenaline in rat cerebral cortex slices in vitro. The drugs, in a wide range of concentrations, did not interfere with the uptake and retention of 3H-noradrenaIine nor did they change the spontaneous release when slices, preincubated with 3H-noradrenaline, were rinsed together with the drug. The field stimulation-induced release of 3H-noradrenaline was also unaffected by these drugs. Pentobarbitone did not affect the amphetamine-induced release of 3H-noradrenaline from the slices. Previous findings show that barbiturates and benzodiazepines decrease the turnover of noradrenaline in the cerebral cortex. The present results make it improbable that this turnover effect is mediated via a direct effect of the drugs on the noradrenaline nerve terminals.

Increased turnover of norepinephrine in the rat cerebral cortex during stress: Role of the locus coeruleus

The effect of “stress” (electrical foot shocks) on the turnover of norepinephrine in the cerebral cortex (including hippocampus) was studied in rats with an acute unilateral lesion in the area of the locus coeruleus. The noradrenergic nerve terminals in the rat cerebral cortex are mainly supplied by norepinephrine-containing neurones originating in the locus coeruleus. Stress induces an increase of the rate of disappearance of norepinephrine after inhibition of catecholamine synthesis (with α-methyl-( p-tyrosine) and an increased formation of 3-methoxy-4-hydroxyphenylglycol sulphate (a major metabolite of norepinephrine in the brain) in the cerebral cortex; these changes were blocked in the ipsilateral cortex of rats with unilateral lesions in the locus coeruleus. These results suggest that the locus coeruleus plays an important role in mediating the effect of stress on the metabolism of norepinephrine in the cerebral cortex.

Alterations in turnover and endogenous levels of norepinephrine in cerebral cortex following electrical stimulation and acute axotomy of cerebral noradrenergic pathways

The turnover and endogenous levels of norepinephrine (NE) in the cerebral cortex (including the hippocampus) were measured after acute axotomy and electrical stimulation of the ascending NE pathways originating from the locus coeruleus. Acute unilateral axotomy of the dorsal NE pathway induces a small increase of NE in the cerebral cortex (ipsilateral vs. contralateral) and a decreased metabolism of NE (as estimated after synthesis inhibition by α-methyl-p-tyrosine). Electrical stimulation (20 Hz) of the locus coeruleus leads to a rapid decrease of NE levels to about 60% of the controls and new steady state levels of NE were reached in 7.5 min. After terminating the stimulation, the levels of NE in the cerebral cortex returned to normal within about 30 min. Electrical stimulation (20 Hz) of the locus coeruleus, after inhibition of NE synthesis, results in a biphasic decline of NE. The first phase is ended in about 2 min (30% decrease) after stimulation, the second phase persists for at least 30 min. The rate of decline of levels of NE in the cerebral cortex in the first phase is about 10 times higher than the rate of decline of the second phase. These results indicate that the level of NE in the cerebral cortex is in part dependent on the nerve impulse flow through the adrenergic fibres and are in favor of the concept of a multiple storage form for NE in the central nerve terminals.