Stimulation of the hypothalamic-pituitary-adrenal axis and inhibition of growth hormone release via increased central noradrenaline neuronal activity by urethane anaesthesia in the rat: blockade by clonidine.

Computerized gas chromatography-mass spectrometry was used to measure precisely the hypothalamic levels of noradrenaline (NA), dopamine and serotonin together with those of their major neuronal metabolites 3,4-dihydroxyphenylethyleneglycol (DHPG), 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in normal male rats 45 min after stimulation of hypothalamic-pituitary-adrenal function by urethane (1.3 g/kg) administration. Urethane treatment resulted in a significant elevation of central noradrenergic neuronal activity (NNA) as assessed from marked rises in hypothalamic DHPG concentrations and the ratio (DHPG/NA). At the same time there was significant stimulation of ACTH and corticosterone release and inhibition of growth hormone release. These hormonal and central effects of urethane (but not anesthesia) were inhibited when the alpha 2-agonist clonidine (150 micrograms/kg) was co-administered. Urethane had no major effect on hypothalamic dopamine or serotonin status. We propose that the release of ACTH and the suppression of growth hormone release following urethane anaesthesia is a result of activation of central NNA and suggest that the hormonal responses are mediated via hypothalamic noradrenergic facilitation of corticotrophin releasing factor and somatostatin release to the anterior pituitary.

Cardiovascular effects of intracisternal 6-hydroxydopamine and of subsequent lesions of the ventrolateral medulla coinciding with the Al group of noradrenaline cells in the rabbit.

The acute cardiovascular effects of intracisternal injections of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine and 5,7-dihydroxytryptamine and the degree of neurotransmitter depletion achieved by such injections were studied. The two different vehicles used--0.2% ascorbic acid in 0.9% NaCl, or 0.9% NaCl--had little effect on the cardiovascular response to 6-OHDA injections but had a striking effect on levels of noradrenaline (NA) subsequently measured in the thoracic spinal cord. 6-OHDA (600 micrograms kg-1 free base) dissolved in normal saline depleted spinal cord NA to less than 1% of control levels whereas the same dose of 6-OHDA dissolved in ascorbate saline only depleted spinal cord NA to 24% of control levels. The degree of depletion of NA in medulla, pons and hypothalamus was similar in the two groups. Ascorbic acid also appeared to contribute to the non-specific toxicity of intracisternal injections of 6-OHDA. The hypertension and bradycardia that followed lesions of the ventrolateral medulla coinciding with the A1 group of noradrenergic cells (Al lesions) were attenuated in animals in which spinal cord NA had been depleted to 2% of control using 6-OHDA in normal saline. However, pretreatment with 6-OHDA in ascorbate saline, which only reduced spinal cord NA to 23% of control, had no effect on the cardiovascular response to Al lesions. It seems likely that the effects of Al lesions are mediated, at least in part, by NA projections descending within the spinal cord.

Evidence for a bulbospinal serotonergic pressor pathway in the rat brain.

The cardiovascular role of spinal serotonin (5-HT) neurones descending from 5-HT cells near the ventrolateral surface of the medulla oblongata was investigated by stimulating these cells in normal animals and in animals with selective chemical ablation of 5-HT nerves. These laterally placed 5-HT nerves fall within the B1 and B3 groups in the medulla and were identified using immunohistochemistry. 5,7-Dihydroxytryptamine (5,7-DHT) was injected into the lateral cerebral ventricle (i.c.v.) to produce a generalized destruction of central 5-HT pathways, with preliminary intraperitoneal administration of desipramine to prevent depletion of noradrenaline stores. In other experiments, 5,7-DHT was injected directly into the cervical spinal cord, after preliminary treatment with desipramine, to produce selective destruction of spinal 5-HT nerves, confirmed both biochemically and immunohistochemically. Electrical stimulation near the lateral 5-HT cells in the B1 and B3 cell groups elicited pressor responses in control (vehicle-injected) rats; the increase in mean arterial pressure was proportional to the intensity and to the frequency of stimulation. Microinjections of kainic acid or L-glutamate at the same sites also produced an increase in mean arterial pressure. Selective destruction of 5-HT nerves, whether produced by i.c.v. or intra-spinal administration of 5,7-DHT, reduced the magnitude of the pressor response to electrical stimulation by over 50%. These experiments suggest the activity of 5-HT nerve cells adjacent to the ventrolateral surface of the medulla oblongata and projecting to the intermediolateral cell column serves to elevate arterial pressure and maintain vasomotor tone.