Central Noradrenergic Activity Research Articles

Clonidine-induced automutilation in mice as a laboratory model for clinical self-injurious behaviour

Clonidine-induced automutilation in mice was investigated as a putative experimental model for human self-injurious behaviour. Clonidine (20, 50 and 100 mg/kg, ip) produced dose-related self-biting, causing severe automutilation in mice which had been isolated and food-deprived for 24 h. This clonidine-induced behaviour was significantly attenuated by pharmacological treatments which selectively augment central serotonergic or reduce central dopaminergic activity. Conversely, the clonidine effect was potentiated by pharmacological agents which selectively reduce or enhance central serotonergic and dopaminergic activity, respectively. Drug-induced alterations in central noradrenergic or cholinergic activity had no significant effect on the self-mutilatory behaviour induced by clonidine. The automutilation induced by clonidine in mice appears to be a good experimental model for human self-injurious behaviour, since the latter has been posturated to result from serotin deficiency and/or facilitation of central dopaminergic activity.

Mechanisms of 5-hydroxy-L-tryptophan-induced adrenocorticotropin release: a major role for central noradrenergic drive.

The serotonin (5-hydroxytryptamine, 5-HT) precursor 5-hydroxy-L-tryptophan (5-HTP) and 5-HT antagonists, respectively, are able to stimulate and block pituitary adrenocorticotropin (ACTH) release. However, our previous data do not support a role of central serotoninergic systems in the neural control of ACTH release. We thus examined the hypothesis that 5-HTP given either alone or with uptake-blocking drugs such as fluoxetine caused stimulation of ACTH through activation of central noradrenergic neuronal activity (NNA). The hypothesis was tested in normal adult male rats by correlating medial basal hypothalamic NNA and serotoninergic neuronal activity (SNA) with serum ACTH following administration of 5-HTP (20 and 100 mg/kg, i.p.) in the presence or absence of fluoxetine (10 mg/kg, i.p.) or cyproheptadine (10 mg/kg, i.p.). The alpha 2-adrenergic agonist clonidine (150 micrograms/kg, i.p.) was used to inhibit central NNA and to examine the role of alpha 2-adrenoceptors in the actions of serotoninergic drugs. Computerized mass spectrometry was employed to specifically and precisely assay hypothalamic norepinephrine (NE), 3,4-dihydroxyphenylethyleneglycol (DHPG), 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) to obtain indices of hypothalamic NNA (DHPG/NE) and SNA (5-HIAA/5-HT). The administration of fluoxetine/5-HTP stimulated (p less than 0.01) both hypothalamic NNA and ACTH release.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of alpha 1-adrenergic blockade on pulsatile luteinizing hormone, follicle-stimulating hormone, and prolactin secretion in polycystic ovary syndrome.

Central noradrenergic mechanisms may participate in the regulation of pulsatile gonadotropin secretion in women with the polycystic ovary syndrome (PCO). To examine this possibility we measured serum LH, FSH, and PRL concentrations at 10-min intervals and total testosterone and 17 beta-estradiol at 60-min intervals for 8 h basally and during the infusion of the alpha 1-adrenoceptor antagonist thymoxamine (10 micrograms/kg X min) in 10 young women with PCO. Mean and integrated serum LH concentrations as well as LH pulse frequency were not significantly altered (P = NS) during the thymoxamine infusion. However, we found an increase in LH pulse amplitude as both net (P less than 0.002) and percent (P less than 0.002) increment, as well as mean LH peak values (P less than 0.05) during alpha 1-adrenergic blockade. There were no significant changes in pulsatile FSH and PRL secretion or gonadal sex steroids during these experimental conditions. These data suggest that in PCO patients, 1) brain noradrenergic mechanisms do not play a stimulatory role in regulating the frequency of pulsatile LH secretion, 2) central noradrenergic activity inhibits LH pulse amplitude, and 3) PRL and FSH pulsatility are not altered by central noradrenergic blockade.

Relationships between catecholamine or 3-methoxy 4-hydroxy phenylglycol changes and the mental performance under submaximal exercise in man.

Eleven young students were tested to determine the relationship between the improvement of mental performances observed under prolonged submaximal work and central or peripheral catecholamine changes. The subjects pedaled a bicycle ergometer for 1 h at a work load individually calculated to approximate 75% of maximal oxygen uptake. The mental test, consisting of 1-h sessions of time-limited word tests and arithmetical calculations, required a high degree of concentration (vigilance and short-term memory). Catecholamines [epinephrine (E), norepinephrine (NE), dopamine (DA)], metanephrine (MN), normetanephrine (NMN) and the glucuronide conjugate of 3-methoxy 4-hydroxyphenylglycol (MHPG) were assayed in urine to assess peripheral activity: E and MN as indexes of adrenomedullary secretion, NE, NMN and MHPG glucuronide as markers of NE metabolism in sympathetic nerves. Urinary MHPG sulfate was determined as a possible marker of central noradrenergic metabolism. When compared to the effect of single tests, the combination of prolonged submaximal work and mental task induced significant increases in MHPG sulfate and E + MN excretions. Both these increases were correlated each to one another and also correlated to the number of discriminated words. Altogether, the present data show that prolonged submaximal work under mental load activates catecholamine systems and suggest that a relationship exists between adrenomedullary activation and the improvement of mental performance. Based on literature data, the possible modulatory role of peripheral E on mental processes and central noradrenergic activity is discussed.

Cerebrospinal Fluid Norepinephrine Levels in Essential Hypertension: Effects of Drug Treatment and Withdrawal

Measurements of cerebrospinal fluid (CSF) catecholamines (CA) were made in an attempt to estimate the activity of central CA neurons in essential hypertension (EHT). CSF norepinephrine (NE), epinephrine (EPI), and dopamine (DA) levels were measured in 12 normotensive (age 36 ± 3 years; SBP = 116 ± 4 and DBP = 79 ± 4 mm Hg) and in 12 EHT (age 41 ± 2 years; SBP = 163 ± 5 and DBP = 107 ± 3 mm Hg) subjects. CSF NE levels were twofold higher in EHT (240 ± 23 pg/ml) than in normotensive subjects (127 ± 28 pg/ml). Very low EPI and DA levels were observed in both groups of patients. The results suggest that central (spinal?) noradrenergic activity is increased in patients with EHT. In a second study we evaluated the effects of clonidine treatment for 2 weeks (150 μg t.i.d.) on CSF NE in EHT. Clonidine reduced pretreatment BP and CSF NE levels by 27% (p < 0.05) and 39% (p < 0.01), respectively. The results of the study indicate that central noradrenergic activity is reduced during clonidine treatment. A third group of experiments was designed to compare the effects of clonidine with those of propranolol treatment in patients with EHT. CSF NE measurements were made after 1 month of treatment with 0.36 ± 0.07 mg of clonidine daily or 160 mg of propranolol daily. CSF NE levels were significantly lower in the clonidine group (p < 0.01). Seventy-two hours after abrupt discontinuation of clonidine or propranolol treatment, BP returned to pretreatment levels. However, CSF NE showed a threefold increase after clonidine withdrawal, and no change after propranolol withdrawal. CSF EPI was not affected by either treatment. These results suggest that neither the reduction in BP produced by propranolol nor the BP raise after propranolol discontinuation is mediated by changes in the central (spinal?) noradrenergic activity. For clonidine, on the other hand, treatment and withdrawal lead to marked changes in CSF NE levels.

Role of the Central Ascending Noradrenergic System in the Regulation of Luteinizing Hormone Responsiveness to Testosterone Negative Feedback in the Adult Male Rat1

It is well established that testosterone (T) feeds back on the brain and the anterior pituitary to inhibit gonadotropin secretion. However, the precise mechanism by which T exerts its central inhibitory action is poorly understood. We hypothesized that central noradrenergic activity decreases hypothalamic sensitivity to T negative feedback. To test this hypothesis, we compared the dose-response relationships between T and luteinizing hormone (LH) and between T and follicle-stimulating hormone (FSH) in adult male rats chronically depleted of hypothalamic norepinephrine (NE) to the dose-response curves exhibited by control animals. Depletion of hypothalamic NE was achieved by two independent methods: 1) by bilateral transection of the ascending noradrenergic system at the level of the mesencephalon, and 2) by intracerebroventricular infusion of the neurotoxin, 6-hydroxydopamine. After allowing 2-3 weeks for recovery from this initial surgery, all animals were castrated, and 3 weeks later were outfitted with subcutaneous T-containing or empty (sham) implants for a period of 48 hours. We observed that despite a profound chronic reduction in hypothalamic noradrenergic activity, the dose-response relationship between plasma T and the gonadotropins remained unaltered. These data demonstrate that normal amounts of hypothalamic noradrenergic activity are not essential for T to exert its negative feedback effect on gonadotropin secretion. Furthermore, they suggest that chronic removal of hypothalamic NE does not alter gonadotropin sensitivity to T negative feedback.

Inhibition of carrageenin-induced pedal oedema in rats by immobilisation stress.

The effect of immobilisation stress on acute pedal inflammation induced by carrageenin, and the mechanism of stress-induced anti-inflammatory effect, were investigated in male Wistar strain albino rats. Carrageenin-induced pedal inflammation oedema was attenuated by immobilisation stress in a time-dependent manner, when the rats were restrained for 30 min, 1 h, and 2 h immediately after the induction of the inflammation. Pentobarbitone exhibited significant anti-inflammatory effect of its own in an anaesthetic dose and also inhibited stress (1 h)-induced attenuation of the inflammation. Likewise, lignocaine, injected behind the knee joint of the inflamed limb, attenuated the inflammation and also inhibited the stress-induced anti-inflammatory effect. These findings indicate the importance of the central nervous system (CNS) and the afferent/efferent neural pathways from and to the inflammatory site, in inflammation and in stress-induced anti-inflammatory effect. Earlier studies from this laboratory have shown that the central noradrenergic, histaminergic, serotonergic and GABA-ergic neurotransmitter systems have a modulatory anti-inflammatory effect on carrageenin-induced pedal oedema. Since all these neurotransmitter systems have been reported to be activated by stress, their role was assessed in the inflammation-attenuation effect of immobilisation stress. The present studies indicate that, of these neurotransmitters, only the central noradrenergic system is involved in the anti-oedema effect of stress. Endogenous opioid peptides may also be involved in the stress-inflammation interaction, since naloxone inhibited the stress effect. Bilateral adrenalectomy and peripheral chemical sympathectomy, induced by i.p. administration of 6-hydroxydopamine, augmented carrageenin oedema and antagonised the stress-induced anti-inflammatory effect. However, metyrapone, an inhibitor of endogenous corticoid synthesis, failed to inhibit the stress effect. These findings indicate that the sympatho-medullary system, which is known to be activated during stress, is responsible for the observed anti-inflammatory effect of immobilisation stress, rather than augmented release of adrenal corticoids. It is suggested that the observed inflammation reducing effect of immobilisation stress is a consequence of increased central noradrenergic and peripheral sympatho-medullary activity.

Effects of the α 2-antagonist idazoxan on monoaminergic parameters measured in the cerebrospinal fluid of rabbits

The α 2-antagonist idazoxan was administered intravenously to rabbits. The increase in central noradrenergic, dopaminergic and serotonergic activity was followed as a function of time by determining neuronal parameters in the cerebrospinal fluid (CSF) and was compared with changes previously determined after yohimbine. These parameters include the enzyme dopamine-β-hydroxylase (DβH), the noradrenergic metabolites 3-methoxy-4-hydroxyphenyl-mandelic acid (VMA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the dopaminergic metabolite 3-methoxy-4-hydroxyphenylacetic acid (HVA) and the serotonergic metabolite 5-hydroxyindole acetic acid (5-HIAA). Control experiments with physiological saline were also performed. DβH activity increased to 211% in control experiments, and to 570 and 530%, respectively after yohimbine and idazoxan. Compared to the control experiments yohimbine was able to elevate VMA, MHPG and HVA concentrations, but 5-HIAA levels were reduced. Idozoxan caused increased MHPG concentrations, slight increases in VMA, little effect on HVA and no effect on 5-HIAA levels. We conclude that idazoxan was as potent as yohimbine as an α 2-antagonist in our in vivo experiments and that idazoxan shows a much greater selectivity with regard to the noradrenergic system.

Chronic sodium depletion suppresses the area postrema pressor pathway

Sodium depletion in dogs is known to affect both the renin-angiotensin as well as the sympathetic nervous system. The effect of this dietary regime upon the area postrema pressor pathway, as evaluated by the cardiovascular responses to centrally acting angiotensin II, has not been determined previously. With this in mind, male mongrel dogs were maintained on Either a normal or a sodium restricted diet supplemented with furosemide and dose-response curves for intravertebral and intravenous angiotensin II (range: 1–20 ng/kg/min) were obtained. Sodium depletion results in not only a blunted intravenous pressor response to angiotensin II but also the abolition of the centrally mediated pressor responses mediated by the area postrema. Because accumulating evidence indicates that in sodium depleted dogs sympathetic nerve activity is reduced while central noradrenergic inhibitory activity is increased the reduced effects of angiotensin II upon the central sympathetically mediated pressor response may in part be related to decreases in sympathetic nerve activity.

Benzodiazepines, plasma MHPG and alpha-2-adrenoceptor function in man.

The effects of a single (15 mg) dose of diazepam, a 3-week course of diazepam (25 mg/d) and its withdrawal on plasma MHPG and the reduction produced by clonidine (1.5 micrograms kg-1 i.v.) were studied in 8 male volunteers. Chronic diagram reduced, but not significantly, plasma MHPG and attenuated the reduction produced Gyclonidine. During the withdrawal phase MHPG levels were significantly enhanced and the lowering produced by clonidine was also greater. These results support the hypothesis that some aspects of benzodiazepine withdrawal may reflect excessive central noradrenergic activity.

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.

Clonidine reverses the behavioral and respiratory effects of continuous naloxone infusion

Opiate naive rats received 24 hours of continuous suncutaneous infusion of 0.67 mg/kg/hr naloxone via osmotic minipump. As in previous studies, this induced an opiate-abstinence-like syndrome of significantly increased oxygen consumption and behavioral signs (wet-dog shakes, abdominal writhes, etc.). Clonidine, which selectively reduces central noradrenergic activity, has been shown to reverse opiate abstinence syndrome. Subcutaneous injection of 0.033 and 0.01 mg/kg clonidine totally reversed the abstinence-like behaviors and respiratory activity induced by naloxone infusion. This constitutes an additional point of similarity between opiate abstinence syndrome and the “endorphin blockade syndrome” or withdrawal from endogenous opioids resulting from chronic naloxone treatment. It is consistent with the hypothesis that hyperactivity of central noradrenergic mechanisms may contribute to both phenomena.

Correlational analysis of central noradrenergic neuronal activity and sympathetic tone in behaving cats.

The activity of the noradrenergic (NA) neurons of the feline locus coeruleus complex (LCx) were correlated with changes in peripheral sympathetic tone in behaving cats. LCx NA neurons exhibit stereotypical changes in discharge rate across behavioral states, falling virtually silent during paradoxical sleep (PS). Simultaneous recordings from LCx NA neurons and the cervical sympathetic trunk demonstrated a tonic reduction in nerve activity during PS as well. LCx NA neurons were also found to fall silent during induction of the scruff immobility reflex and significant pupillary miosis was seen during this behavior as well. These data support the hypothesis that NA neurons in the brain are a central analogue of the peripheral sympathetic system and demonstrate that the two systems operate in an integrated fashion in the behaving cat.

Possible mechanisms for lactate's induction of panic.

Forty-three patients with panic disorder or agoraphobia with panic attacks and 20 control subjects received 0.5 M racemic sodium lactate intravenous infusions, single-blind as to duration and sequence. During the procedure, pulse; blood pressure; blood L-lactate and pyruvate; plasma ionized calcium, phosphate, prolactin, epinephrine, norepinephrine, and cortisol levels; and venous PCO2, pH, and bicarbonate were measured in an attempt to clarify the mechanism of lactate-induced panic attacks. During the infusion, 72% of the patients but none of the control subjects had panic attacks. The laboratory findings suggest that peripheral catecholamine surge is not the mechanism by which lactate causes panic, although elevated epinephrine may be a predisposing factor. Heightened central noradrenergic activity was present in many but not all of the attacks. Contrary to previous hypotheses, neither depression of ionized calcium nor induction of metabolic alkalosis appears sufficient to cause panic during lactate infusion.

Noradrenergic changes and memory loss in aged mice

The present paper addresses the question of whether a decline of central noradrenergic activity is associated with aging and memory loss in mice. Receptor binding techniques were utilized to compare alpha 2-adrenoceptor density in the brains of aged and young mice. Using [3H]rauwolscine, a selective alpha 2-adrenoceptor antagonist, two membrane binding sites were identified which were differentially affected by age. Whereas the density of high-affinity binding sites was unchanged in aged brain as compared to young controls, there was a significant decrease in the number of low-affinity sites. In a separate study, animals were tested for performance on a step-through inhibitory avoidance task, prior to sacrifice and morphological analysis of the brainstem noradrenergic nucleus locus coeruleus (LC). Aged mice exhibited a significant decrease in task retention as compared to young controls; a small, though non-significant, decline was also observed in the numbers of cells within LC. While young mice exhibited low within-group variance, individual aged animals differed greatly in both LC cell number and behavioral performance. Within the aged population, there was a highly significant correlation between the extent of LC cell loss and the degree of memory impairment. These results provide further evidence for an age-related decline in central noradrenergic function which may contribute to an associated memory loss.

Recovery of pulsatile luteinizing hormone secretion following permanent disruption of the ascending noradrenergic fiber tract in the ovariectomized rat.

To determine whether noradrenergic (NE) support was essential for the generation of pulsatile luteinizing hormone (LH) secretion, we studied the effect of acute and chronic disruption of central noradrenergic pathways on patterns of LH release in the ovariectomized female rat. We argued that if NE pathways were essential for the generation of pulsatile LH secretion, then disruption of central NE activity should effect a blockade of LH pulses. To test this hypothesis we chronically disrupted NE activity by transecting the ascending NE pathway (ANP) and acutely disrupted NE activity by administering the alpha-adrenergic receptor blocking agent phenoxybenzamine (PBZ); and we evaluated the effect of these treatments on the pattern of pulsatile LH secretion. Four weeks after the ANP transections, we found no differences in either LH pulse amplitude or frequency between ANP-cut animals (n = 6) and sham-cut controls (n = 8). In sham-cut animals (n = 7), PBZ reduced LH pulse frequency by 85% (P less than 0.002) and had no effect on pulse amplitude. In contrast, PBZ was significantly less effective in reducing LH pulse frequency in ANP- cut rats (n = 9); pulse frequency in these animals was 4 times greater than that found in PBZ-treated, sham-cut rats. We conclude from these data that, whereas noradrenergic pathways usually interact with LH regulatory mechanisms, they are not essential for the generation of normal gonadotropin-releasing hormone pulses.

The formation of deaminated metabolites of dopamine in the locus coeruleus depends upon noradrenergic neuronal activity

The effect of manipulations of noradrenergic neuronal activity on the levels of the deaminated metabolites of dopamine in the locus coeruleus has been investigated in the rat. Antidromic stimulation of the locus coeruleus increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MOPEG) in this area. Conversely, local infusion of tetrodotoxin into the locus coeruleus reduced the levels of these metabolites in this region. After systemic injection, idazoxan increased whereas clonidine diminished DOPAC, HVA and MOPEG levels in the locus coeruleus either in normal animals or in animals bearing a lesion of A9 and A10 dopaminergic cells. These results suggest that the formation of dopamine deaminated metabolites in noradrenergic cell bodies is dependent upon, and may serve as an index of, central noradrenergic neuronal activity.

The clinical syndrome of striatal dopamine deficiency. Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a syndrome that resembles Parkinson's disease. To compare the biochemical abnormalities produced by this compound in human beings with those occurring in Parkinson's disease, we examined biogenic amine metabolites in cerebrospinal fluid and urine from six patients with MPTP-induced parkinsonism and eight patients with Parkinson's disease. In both forms of parkinsonism, the cerebrospinal fluid levels of homovanillic acid, the major metabolite of dopamine, were reduced, whereas the levels of the serotonin metabolite 5-hydroxyindoleacetic acid were normal. The cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the major metabolite of norepinephrine in the brain, after adjustment for plasma MHPG, were elevated (greater than 6.0 ng per milliliter) in MPTP-induced parkinsonism, whereas MHPG levels were reduced (less than 6.0) in Parkinson's disease. Neurons containing norepinephrine in the brain are involved in the degenerative process of Parkinson's disease, whereas they are spared in MPTP-induced parkinsonism. The selective destruction by MPTP of nigrostriatal dopamine neurons that is responsible for the movement disorder also appears to result in an increase in central noradrenergic activity, which is not possible in Parkinson's disease. Thus, differences in central noradrenergic activity, reflected in cerebrospinal fluid levels of MHPG, distinguish these two forms of parkinsonism.

CSF dopamine-beta-hydroxylase activity in Parkinson's disease.

Although the most prominent neurochemical change in parkinsonism is nigrostriatal dopamine deficiency, norepinephrine content is also diminished in the CNS. In this study, dopamine-beta-hydroxylase (DBH) activity, a marker of central noradrenergic activity, was measured in the CSF of previously unmedicated parkinsonian patients and normal controls. The parkinsonian patients showed a reduction in CSF DBH levels to 41% of control values (p less than 0.01). Possible explanations for the decrease included a decreased noradrenergic nerve pool or a diminished rate of synthesis of catecholamines.

Precipitated diazepam withdrawal elevates noradrenergic metabolism in primate brain

Following treatment for seven days with diazepam (2.0 mg/kg i.m., b.i.d.), administration of the benzodiazepine receptor antagonist RO 15-(5 mg/kg) induced a severe withdrawal syndrome in vervet monkeys which included tremors, vomiting, vocalizations, chewing, and piloerection. Brain concentrations of the noradrenergic metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were significantly higher in the precipitated withdrawal group than in the diazepam plus vehicle control group. Administration of RO 15- without prior diazepam treatment had no effect on brain MHPG, nor did it produce withdrawal behaviors, but did produce an increase in the frequency of scratching. These results raise the possibility that increased central noradrenergic activity serves a role in benzodiazepine withdrawal similar to the role hypothesized for noradrenergic activity in opiate withdrawal.