Hypothalamic Noradrenergic Neurons Research Articles

When Immune-Neuro-Endocrine Interactions Are Disrupted: Experimentally Induced Arthritis as an Example

We studied whether, in parallel to the activity of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the development and chronification of arthritis induced by immunization of rats with type II collagen. Corticosterone levels were increased only transiently, and were even below the normal range as the disease progressed. Increased adrenaline blood levels and hypothalamic IL-1β and IL-6 overexpression were observed only during the induction phase of the disease. The increase in hypothalamic noradrenaline content during the symptomatic phase was paralleled by a gradual loss of sympathetic fibers in the joints. Depletion of hypothalamic noradrenergic neurons at this time did not affect the symptomatology. Contrary to observations in healthy animals, no correlation between hypothalamic IL-1β expression and noradrenaline content was observed in rats with arthritis. The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate that the communication between afferent immune messages to the central nervous system and two main efferent anti-inflammatory pathways under control of the brain are disrupted during experimental arthritis.

Disrupted brain–immune system–joint communication during experimental arthritis

To explore the hypothesis that, in parallel with alterations in the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the course of arthritis development induced by type II collagen. This hypothesis was based on evidence that acute inflammatory processes induce cytokine expression in the brain and affect neuronal activity. We also studied whether depletion of hypothalamic noradrenaline can affect peripheral joint disease. Hypothalamic cytokine gene expression and neurotransmitter concentration, parameters of inflammation, and joint innervation were evaluated during arthritis development in rats induced by injection of type II collagen in Freund's incomplete adjuvant. Noradrenergic neurons in the brain were depleted with 6-hydroxydopamine. Transiently increased corticosterone levels, followed by increased adrenaline levels and hypothalamic interleukin-1beta (IL-1beta) and IL-6 overexpression were observed only during the induction phase of the disease. Hypothalamic noradrenaline content was increased during the symptomatic phase and was paralleled by a gradual loss of noradrenergic fibers in the joints. The positive correlation between hypothalamic IL-1beta expression and noradrenaline content in control groups was not observed in rats in which arthritis developed. Depletion of hypothalamic noradrenergic neurons when arthritis was established did not affect the course of the disease. The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate a disruption in communication between afferent immune messages to the central nervous system and 2 main efferent antiinflammatory pathways under control of the brain during collagen-induced arthritis.

Transforming growth factor-beta in the brain enhances fat oxidation via noradrenergic neurons in the ventromedial and paraventricular hypothalamic nucleus

We have previously reported that intracisternal administration of TGF-beta induces an increase in fat oxidation and that intracisternal administration of anti-TGF-beta antibody partially inhibits an increase in fat oxidation during treadmill running in rats. These results indicate a regulatory role of that TGF-beta in the brain on fat oxidation during exercise. However, it is not clear how TGF-beta in the brain enhance fat oxidation. We hypothesized that TGF-beta in the brain elicits its regulatory effects on fat oxidation via hypothalamic noradrenergic neurons, because some reports have demonstrated the important role of hypothalamic noradrenergic neurons in the regulation of fat oxidation during and after exercise. To examine this hypothesis, we measured the extracellular noradrenaline (NA) levels in the paraventricular hypothalamic nucleus (PVH), ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic area, which are especially important in the regulation of energy metabolism, after intracisternal administration of TGF-beta by using an in vivo brain microdialysis. Microdialysis study revealed that intracisternal administration of TGF-beta3 caused increases in the NA levels in the PVH and VMH. Then, we investigated the impact of impairment of noradrenergic neurons in the PVH and VMH by neurotoxin 6-hydroxydopamine microinjection (NA-lesion) on the action of intracisternal administration of TGF-beta. The NA lesion completely abolished the regulatory effect of TGF-beta on fat oxidation. These results suggest that TGF-beta in the brain enhances fat oxidation via noradrenergic neurons in the PVH and VMH.

Centrally applied nitric oxide donor elevates plasma corticosterone by activation of the hypothalamic noradrenergic neurons in rats

The present study was undertaken to investigate the mechanisms involved in a nitric oxide donor [3-morpholino-sydnonimine (SIN-1)]-induced activation of hypothalamic–pituitary–adrenal axis in urethane- and α-chloralose-anesthetized rats. Intracerebroventricularly (i.c.v.) administered SIN-1 (250 and 500 μg/animal) effectively and dose-dependently elevated plasma levels of corticosterone. Pretreatment with phentolamine (250 μg/animal, i.c.v.), an α-adrenoceptor antagonist, attenuated the elevation of plasma corticosterone evoked by SIN-1, but sotalol (300 μg/animal, i.c.v.), a β-adrenoceptor antagonist, was without effects. The same doses of SIN-1 also increased the release of noradrenaline in the hypothalamic paraventricular nucleus (PVN) measuring microdialysis technique, and this increase was abolished by tetrodotoxin (1 μM) administered into the perfusion solution of the PVN. Furthermore, pretreatment with indomethacin (500 μg/animal, i.c.v.), a cyclooxygenase inhibitor, abolished the SIN-1-induced elevations of both noradrenaline in the PVN and plasma corticosterone. These results suggest that i.c.v. administered SIN-1 activates central noradrenergic neurons innervating the PVN by prostaglandin-mediated mechanisms. Released noradrenaline in the PVN elevates plasma levels of corticosterone via an activation of the central α-adrenoreceptors in rats.

Octreotide-induced suppression of the hyperglycemic response to neostigmine or bombesin: relationship to hypothalamic noradrenergic drive

Neostigmine (cholinesterase inhibitor) or bombesin, when injected into the third cerebral ventricle of awake rat, dose-dependently increased serum glucose with the simultaneous rise in hypothalamic noradrenergic neuronal activity (NAA). Co-administration of octreotide with neostigmine or bombesin suppressed the hypothalamic NNA response with the simultaneous inhibition of the hyperglycemic response. There was a close relationship between hypothalamic NNA and serum glucose in these studies. On the basis of the concept that hypothalamic noradrenergic drive plays an important role in mediating the hyperglycemic response to stressful stimuli, the present findings suggest that the hyperglycemic response to neostigmine or bombesin is mediated via the interaction with hypothalamic noradrenergic neurons.

Effects of morphine and U-50,488H on neurochemical activity of the hypothalamic noradrenergic neurons and pituitary-adrenal response

We examined the ability of morphine and U-50,488 H administered acutely to the rat to modify the hypothalamic noradrenaline (NA) content and turnover as well as corticosterone release. Hypothalamic NA and its metabolite 3-methoxy-4-hydroxy-phenylethylen glycol (MHPG) were determined by high-performance liquid chromatography (HPLC). Plasma corticosterone was measured by radioimmunoassay (RIA). The administration of morphine (30 mg/kg i.p.) induced a decrease in the hypothalamic content of NA, with an enhancement in the MHPG and the MHPG/NA ratio. Similarly, the administration of U-50,488 H (15 mg/kg i.p.) produced an increase in the MHPG and MHPG/NA ratio without any changes in the NA content. The present results also show that corticosterone secretion was increased after acute morphine or U-50,488 H, in parallel with an enhanced NA turnover and strongly suggest that noradrenergic neurons have stimulatory effects on the HPA axis activity, reflecting an indirect action of opioid on the axis through hypothalamic catecholaminergic systems.

Swimming stress that causes hyperglycemia increases in vivo release of noradrenaline, but not acetylcholine, from the hypothalamus of conscious rats

The effects of acute swimming stress (10 min) on noradrenaline release from the medial basal hypothalamus (MBH; consisting of the ventromedial and dorsomedial hypothalamus) and acetylcholine release from the lateral hypothalamic area (LHA) were investigated in freely moving rats by using in vivo microdialysis techniques. Serum glucose, noradrenaline and adrenaline concentrations were also determined. Acute swimming stress produced significant hyperglycemia, with increases in serum noradrenaline and adrenaline concentrations. The release of noradrenaline from the MBH was significantly stimulated during the swimming stress. On the other hand, the swimming stress has no significant effect on the release of acetylcholine from the LHA. These findings support the idea that hypothalamic noradrenergic neurons play an important role in the sympathoadrenal hyperglycemic response to stressful stimuli. Moreover, it is suggested that hypothalamic cholinergic neurons are not involved in the responses of serum glucose, noradrenaline and adrenaline concentrations to swimming stress.

Modulation by catecholamine of hypothalamus-pituitary-adrenocortical (HPA) axis activity in morphine-tolerance and withdrawal

1. 1. Hypothalamic noradrenaline (NA), dopamine (DA) and plasma cortiocosterone concentrations were determined after acute morphine administration to both naive and morphine-tolerant rats and during naloxone-induced withdrawal. 2. 2. Acutely administered morphine (30 mg/kg) significantly increased the plasma level of corticosterone and reduced the NA and DA content in the hypothalamus. Naloxone (1 mg/kg), administered before morphine, blocked the effect of the opiate on both plasma corticosterone and hypothalamic NA concentration. 3. 3. In chronically morphine-treated rats, a challenge dose of morphine (30 mg/kg) neither modified the plasma corticosterone level nor the NA concentration, while DA content was significantly enhanced. 4. 4. After naloxone-induced withdrawal, the hypothalamic content of NA was significantly reduced, simultaneously with an increase in plasma corticosterone, while DA content remained unchanged. 5. 5. These results suggest that the hypothalamic noradrenergic neurons are mainly implicated in the effect of acute morphine on the hypothalamus-pituitary-adrenocortical (HPA) axis and in the tolerance development to this effect. The results also suggest that a hyperactivity of noradrenergic pathways in the hypothalamus would be one of the physiologically relevant mechanisms mediating the neuroendocrine opiate withdrawal at the HPA level.

Morphine increases hypothalamic noradrenaline turnover but rather decreases its enhancement induced by stress in rats.

By measuring levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), we investigated the effects of morphine on hypothalamic noradrenergic neurons in stressed or non-stressed states in male rats. Subcutaneous administration of morphine at 3 mg/kg and 6 mg/kg reduced NA level and elevated MHPG-SO4 level in the hypothalamus in a dose-dependent manner and these effects of morphine were completely abolished by pretreatment with naloxone at 0.5 mg/kg and 5 mg/kg (s.c.). Immobilization stress caused significant reduction of NA and increase in MHPG-SO4 level, and this stress-induced increase in NA turnover was attenuated by pretreatment with 3 mg/kg and 6 mg/kg of morphine. Attenuation of stress-induced enhancement of hypothalamic NA turnover by morphine was almost completely reversed by naloxone at 0.5 mg/kg and 5 mg/kg. These results suggest that morphine produces different effects on hypothalamic noradrenergic neurons, depending on the state of the animal treated, i.e., facilitation in the non-stressed state and inhibition in the stressed state and that these actions occur via opiate receptors. It is further suggested that the hypothalamic opioid peptide system might be partially involved in the stress process by attenuating increased NA turnover by stress in rats.

The Role of Hypothalamic Noradrenergic Neurons in Food Intake Regulation

This chapter discusses the role of hypothalamic noradrenergic neurons in food intake regulation. To investigate the differential involvement of adrenergic neurons in different parts of the hypothalamus the chapter mentions experiments in which catecholaminergic systems in different loci is selectively destroyed by means of 6-hydroxydopamine (6-OHDA). A specific technique used in investigating hypothalamic neural systems is the technique of injecting small amounts of chemicals that are known to affect in a specific way a particular type of neuron, directly into the hypothalamus and then observe their effects in anaesthetized and unrestrained subjects. A chronic cannula is implanted in the brain that allows for repeated drug injections into a specific site when the animal has recovered from the operation. The hypothesis of an inhibitory action of the 8-receptors rests upon the concept of the LH as a “feeding” center, a concept that has originated mainly because lesions in the lateral hypothalamus caused aphagia and adipsia, and because electrical stimulation of the LH caused stimulus bound eating.