Central Noradrenergic Neurons Research Articles

Central noradrenergic neurones and the cardiovascular actions of clonidine in the rabbit.

1. Clonidine (1 mug/kg), given by intracisternal injection to anaesthetized rabbits, lowered mean arterial blood pressure by 33 mmHg and heart rate by 32 beats/min.2. In animals pre-treated with 6-hydroxydopamine (6-OHD 500 mug/kg intracisternally) 7-10 days before, intracisternal clonidine (1 mug/kg) reduced mean arterial blood pressure by only 2.5 mmHg and heart rate by 4 beats/minute.3. The hypotensive action of intravenous clonidine was reduced to 49% of control by pre-treatment with intracisternal 6-OHD. In unanaesthetized normal animals intravenous clonidine (30 mug/kg) lowered mean arterial blood pressure by 19.3 mmHg, while after 6-OHD it fell only 9.4 mmHg.4. These studies suggest that the central hypotensive effect of clonidine is dependent on the integrity of central monoaminergic neurones.

Alpha-receptor-mediated modulation of transmitter release from central noradrenergic neurones.

Slices of rat cerebral cortex were preincubated with 10−7 M (-)-3H-noradrenaline, and the outflow of tritium was determined. Oxymetazoline, phentolamine and cocaine did not change the spontaneous efflux. The overflow of tritium evoked by electrical field stimulation was decreased by oxymetazoline, and enhanced by phentolamine, phenoxybenzamine, and cocaine. Oxymetazoline did not counteract the increase of the stimulation-induced overflow caused by cocaine, but strongly antagonized the increase caused by phentolamine and phenoxybenzamine. When the stimulation-induced overflow was large under control conditions (high frequency of stimulation, addition of cocaine), the inhibitory effect of oxymetazoline was diminished. The results indicate that an α-receptor-mediated feed-back control of noradrenaline release, previously demonstrated in postganglionic sympathetic nerves, also operates in central noradrenergic neurones.

Effect of stress on various characteristics of norepinephrine metabolism in central noradrenergic neurons.

Possible relationships between various physiological states, aggressive behaviour or emotions and biogenic amines have generated considerable scientific interest. Studies, in several species, reported during the past few years indicated that physical stress is associated with alterations in the metabolism of norepinephrine (NE) in the rat brain.KeywordsTyrosine HydroxylaseNoradrenergic NeuronFunctional PoolNorepinephrine MetabolismBrain Stem SliceThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Acute effects of 6-hydroxydopa on central monoaminergic neurons

The effect of 6-hydroxydopa (6-OHDOPA) on mouse whole brain monoamines was studied. It was shown that i.v. administration of a 100 mg/kg dose of 6-OHDOPA reduced whole brain norepinephrine (NE) by 35% after 24 hr, while dopamine (DA) levels were unchanged. With a 150 mg/kg dose whole brain NE levels were reduced by 70% after 3 hr and 55% after 24 hr; whole brain DA content was reduced by 15–20% at both time periods. The effects of 6-OHDOPA (150 mg/kg, i.v.) on NE depletion in the brain could be prevented by d- and l-amphetamine, desipramine and chlorpromazine. MK-486, a peripherally acting dopa decarboxylase inhibitor, potentiated NE depletion by 6-OHDOPA in the brain. While 6-OHDOPA had no effect on monoamine oxidase and choline acetylase activity in the ‘cortex’, brainstem and cerebellum, catechol-O-methyl transferase activity was reduced in the brainstem after 14 days and acetylcholinesterase activity was reduced in the ‘cortex’ after 2 and 14 days. It is concluded that moderate doses of 6-OHDOPA have a marked effect on central noradrenergic neurons, while dopaminergic neurons remain intact.

Altered ontogenesis of central noradrenergic neurons following neonatal treatment with 6-hydroxydopamine

Altered ontogenesis of central noradrenergic neurons following neonatal treatment with 6-hydroxydopamine

Participation of central noradrenergic neurons in arterial baroreceptor reflexes in the rabbit. A study with intracisternally administered 6-hydroxydopamine.

Rabbits were given intracisternal injections of 6-hydroxydopamine (6-OH-DA) that caused selective ablation of central noradrenergic neurons without damaging peripheral sympathetic nerves. Administration of 6-OH-DA (600 µg/kg, intracisternally) to normal rabbits produced a permanent bradycardia of about 30%, which was initiated centrally and mediated mainly through the vagus, and caused a brief reduction in mean arterial blood pressure, which was due to transient withdrawal of alpha-sympathetic tone. Treatment with 6-OH-DA (600 µg/kg) completely prevented the increases in arterial blood pressure seen on the seventh and the fourteenth day after sinoaortic denervation in control rabbits, although there was a transient increase in blood pressure for 1 day after denervation in the group treated with 6-OH-DA. Central norepinephrine concentrations were reduced in all areas, especially in the spinal cord (to less than 10% of control), in the denervated rabbits treated with 6-OH-DA compared with the levels in denervated controls. When 6-OH-DA (600 µg/kg, intracisternally) was given to rabbits with neurogenic hypertension produced by buffer nerve section, it caused an immediate and persistent return of pressure to the level that existed before denervation. Probably, the integrity of central noradrenergic neurons is necessary for the development of sustained increases in arterial blood pressure following sinoaortic denervation. We suggest that central noradrenergic nerves form an essential link in the baroreceptor reflex arc, possibly at the bulbospinal level.

The use of dopamine -hydroxylase as a marker for the central noradrenergic nervous system in rat brain.

Improvements in the method for localization of dopamine-beta-hydroxylase by immunofluorescence allow the observation of noradrenergic-cell bodies, non-terminal fibers, and axon terminals in the rat brain. The distribution of the hydroxylase correlated well with the results obtained by localization of norepinephrine. Dopamine-beta-hydroxylase was not observed in dopaminergic neurons or terminals, indicating that these cells do not have the capacity to synthesize norepinephrine. The use of the hydroxylase as a marker, however, has made it possible to visualize noradrenergic nerve terminals on small arteries in the brain parenchyma that have not been described by catecholamine-fluorescence histochemistry. The source of the terminals on small arteries appears to be central noradrenergic neurons rather than the peripheral sympathetic nervous system. Dopamine-beta-hydroxylase generally was not observed in the large arteries of the brain parenchyma. These observations suggest that cerebral microcirculation is regulated by central noradrenergic neurons.

Effects of L-DOPA on the EEG and brain amines of unrestrained rats

When injected intraperitoneally into chronically prepared rats, l-DOPA did not desynchronize the waking EEG until doses in the lethal range were approached. Diethyldithiocarbamate (DDC) also desynchronized the EEG. Yet when DDC and l-DOPA were combined a relative synchrony was observed. After isocarboxazid the threshold dose of l-DOPA for desynchrony was lowered well below the lethal range. d,l-Dihydroxyphenylserine (DOPS) did not alter the EEG, either alone or in combination with isocarboxazid. Pretreatment with U-14,624 or a low dose of Ro 4-4602 did not affect the control EEG or the isocarboxazid- l-DOPA desynchrony. However, after 400 mg/kg Ro 4-4602 (central decarboxylase inhibited), the isocarboxazid- l-DOPA desynchrony was completely attenuated. Analysis of brain amines indicated that only relatively large increases in brain dopamine were correlated with the EEG desynchrony induced by l-DOPA. Alterations in brain 5-hydroxytryptamine after the various drug treatments indicate that interactions involving this brain amine are very complex. The data support the conclusion that a centrally produced decarboxylated metabolite of l-DOPA is responsible for the EEG desynchrony and, tentatively, that this metabolite is dopamine. Nevertheless, the use of dopamine-β-hydroxylase inhibitors (DDC and U-14,624) and DOPS involve complications that compromise their utility as pharmacological tools. The role of other metabolites of l-DOPA and the possiblity that dopamine alters the EEG secondarily by affecting central noradrenergic or serotonergic neurons remain to be explored.

Neurochemistry of reward and punishment: Some implications for the etiology of schizophrenia

Publisher Summary This chapter discusses some implications for the etiology of schizophrenia. Genetic studies provide indirect support for the idea that an impairment of noradrenergic function may be involved in schizophrenia. Several lines of biochemical evidence suggest that 6-hydroxydopamine is the aberrant metabolite that causes schizophrenia. This compound is an autoxidation product and metabolite of dopamine and its formation can occur to a significant extent in the intact animal. 6-Hydroxydopamine induces a specific degeneration of peripheral sympathetic nerve terminals with a marked and long-lasting depletion of norepinephrine. It is found that when injected intraventricularly into the rat brain, 6-hydroxydopamine similarly causes a prolonged or permanent depletion of brain catecholamines. Only catecholamine-containing neurons are affected, and brain norepinephrine is more severely depleted than dopamine. Electron microscopic evidence reveals that norepinephrine nerve terminals in the brain degenerate and eventually disappear after repeated doses of 6-hydroxydopamine. Single doses of 6-hydroxydopamine of 200 μg or less, however, may decrease brain norepinephrine without apparent ultrastructural damage. It is found that despite the profound damage to central noradrenergic neurons, rats treated with 6-hydroxydopamine are reported to be grossly indistinguishable from controls except for a slight decrease in body weight and a lack of self-grooming.