Pharmacological evidence for inhibition of ACTH secretion by a central adrenergic system in the dog

To obtain more information about the transmitter involved in catecholaminergic inhibition of ACTH secretion, the site of this inhibition, and the receptors involved, the secretion of ACTH was studied in pentobarbital-anesthetized dogs that were surgically stressed and treated with drugs which modify central catecholaminergic transmission. The index of ACTH secretion was adrenal venous output of corticoid hormones. Intravenous L-dopa inhibited ACTH secretion, and this inhibition was not modified by blockade of peripheral decarboxylation of L-dopa with carbidopa. Intravenous or centrally administered clonidine inhibited stress-induced ACTH secretion, whereas centrally administered apomorphine did not. When given into the third ventricle, phenoxybenzamine (but not phentolamine) blocked the inhibitory effect of L-dopa and clonidine. Pimozide had no effect. L-propranolol caused a small but significant decrease in stress-induced ACTH secretion. Intraventricular procaine blocked the stress response. The data support the conclusion that the site of catecholaminergic inhibition of ACTH secretion is central, 'inside the blood-brain barrier', instead of the pituitary or the median eminence. They indicate that dopamine is not the mediator involved, and suggest that it is probably norepinephrine, although epinephrine is not ruled out. The receptor on which the released catecholamines act, presumably on the surface of the cells that secrete the hypothalamic hormone that regulates ACTH secretion, appears to be a type of alpha-adrenergic receptor.     

Brain noradrenaline and anaesthesia: behavioural and electrophysiological evidence

Neonatal administration of 6-hydroxydopamine to rat pups was used to deplete brain noradrenaline in the locus coeruleus projection system to less than 5% of normal and the response to barbiturate and non-barbiturate anaesthetics examined. The sleeping time in response to administration of thiopentone, pentobarbitone, methohexitone or hexobarbitone was markedly increased in 6-hydroxydopamine-treated rats, as it was for the non-barbiturates chloral hydrate and diisopropylphenol. The sleeping time for other non-barbiturates such as althesin, ketamine and ethyl carbamate (urethane) was not affected in noradrenaline-depleted rats. Similarly, an index of the evoked potential, recorded in the primary somatosensory cortex to supramaximal electrical stimulation of the forepaw, decreased more markedly with increasing doses of thiopentone in 6-hydroxydopamine-treated rats than in controls. Potentiation of the effect of diisopropylphenol on the evoked cortical response was also seen in noradrenaline-depleted rats while the effect of althesin did not differ. It is suggested that brain noradrenaline pathways originating from the locus coeruleus may play an important role in the duration and depth of anaesthesia resulting from barbiturate and some related agents.     

Enhanced striatal glutamate release after the administration of rimonabant to 6-hydroxydopamine-lesioned rats

While recent studies have shown that the blockade of cannabinoid CB(1) receptors might be beneficial to alleviate the motor inhibition typical of Parkinson's disease (PD), the neurochemical substrates for this effect remain elusive. Here we have carried out microdialysis experiments to determine whether the effects of rimonabant, a selective antagonist of CB(1) receptors, might be associated with changes in striatal glutamate release in a rat model of PD generated by intracerebroventricular injection of 6-hydroxydopamine. Our data demonstrate that the treatment with rimonabant slightly increased striatal glutamate release in control rats, although this effect was only evident with the highest dose of rimonabant tested (1mg/kg). However, the increase in glutamate release was much more marked in the parkinsonian rats where similar changes were observed at a dose of 1 and 0.1mg/kg, exactly the same dose that relieved motor inhibition in previous behavioral studies. In summary, the potential of rimonabant to act as a possible antihypokinetic agent in parkinsonian rats seems to be related to enhanced glutamate release from excitatory afferents to the striatum. This observation is of potential clinical interest, particularly for those parkinsonian patients that exhibit a poor response to classic levodopa treatment.     

Thirst and vasopressin secretion following central administration of angiotensin II in rats with lesions of the septal area and subfornical organ

Various dipsogenic stimuli, including peripheral and central administration of angiotensin II, have been shown to be capable of releasing vasopressin from the neurohypophyseal system. Studies were carried out in the rat to investigate whether the septal area, which contains a high concentration of angiotensin-sensitive cells and has neural connections with hypothalamic vasopressin-secreting neurons, mediated the stimulatory effect produced by angiotensin II on vasopressin release. Rats with electrolytic lesions in the region of the septal area had increased daily water consumption and urine output when these lesions included the medioventral or lateral nuclei of the septal forebrain, but not when the lesion involved the subfornical organ. No difference was observed in drinking responses following water deprivation or intracerebroventricular injection of angiotensin II in all experimental groups. In addition, the impaired ability to maintain water homeostasis (polyuro-polydipsic syndrome) of septal-lesioned rats was associated septal-lesioned rats was associated with decreased levels of circulating radioimmunoassayable vasopressin. Furthermore, the vasopressin release which occurred in response to intracerebroventricular angiotensin II in normal controls, sham-lesioned and subfornical organ-lesioned rats was significantly attenuated in rats with electrolytic lesion of the medioventral or lateral septal area. Since cells in the lateral septal area are excited by iontophoretic application of angiotensin II, the present data might be consistent with the hypothesis that the stimulatory effect produced by central administration of angiotensin II on vasopressin release rests upon the integrity of the lateral septal area.     

Potentiation of inhibition by general anaesthetics in neurones of the olfactory cortex in vitro

Pentobarbitone, phenobarbitone, methohexitone, chloralose and alphaxalone produced 10-fold increases in the duration of an inhibitory post-synaptic conductance (i.p.s.c.) as recorded intracellularly from neurones of the guinea-pig olfactory cortex in vitro. Higher concentrations slightly depolarised these neurones and reduced their input resistances (R_i), presumably a spontaneous activation of the inhibitory conductance. The excitatory potentials were also depressed. Ketamine, halothane and urethane doubled the i.p.s.c. duration. Higher concentrations depressed synaptic activity and the action potential, as did lignocaine. Ketamine also increased R_i. These results confirm the idea that these compounds produced anaesthesia by prolonging inhibition (accompanied by a depression of the e.p.s.p. with some anaesthetics).     

Fine structural evidence for hormone secretion by a human thymic tumour

An epidermoid type of thymoma from an asymptomatic 39-year-old male subject is described. Electron microscopy demonstrated endocrine type secretory granules within the tumour cells, and a minority of these granules resembled normal human pancreatic alpha cell granules. Fine structural evidence for endocrine secretory activity in a primary thymic tumour has not been previously described.There are few fine structural reports of primary thymic tumours in man and to our knowledge these do not include certain features of the case described here.     

Alzheimer病中枢肾上腺素能系统的变化

关于阿尔兹海默病 (Ａｌｚｈｅｉｍｅｒ’ｓｄｉｓｅａｓｅ ,ＡＤ)中枢去甲肾上腺素 (ｎｏｒａｄｒｅｎａｌｉｎ ,ＮＥ)能系统的异常 ,各种报道不尽一致 ,基本上有降低和升高两种情况。蓝斑核ＮＥ能神经元的显著丧失导致脑脊液和皮层及皮层下区域ＮＥ浓度下降 ,这易于理解 ;但有些ＡＤ脑脊液中ＮＥ浓度不变甚至升高 ,这种在体发现似乎与尸检蓝斑核神经元丢失不一致 ,本文着重对此展开综述 ,并对目前临床上与ＮＥ相关的ＡＤ的药物治疗进行归纳和分析。1　ＡＤ患者中枢ＮＥ的变化1 1　ＡＤ患者中枢ＮＥ水平下降　早在 1987年Ｂｏｎ ｄａｒｅｆ…     

Valproic acid sodium inhibits the morphine-induced conditioned place preference in the central nervous system of rats

The present study was performed to investigate the effects of valproic acid sodium (VPA), a widely utilized antiepileptic drug, on the establishment of chronic morphine-induced conditioned place preference (CPP). The rat model of morphine-induced CPP was conditioned with alternating intracerebroventricular (i.c.v.) injections of morphine (60 microg/6 microl) and saline for 5 days. To investigate the influence of VPA on morphine-induced CPP, rats received chronic pretreatment of i.c.v. VPA (500 microg/rat) 10 min previous to the daily morphine injection. The results demonstrated that the morphine-induced CPP was significantly attenuated by VPA pretreatment, while the VPA itself could not induce any CPP or conditioned place aversion (CPA) effects. The results of the present study not only confirmed the reliability of establishing morphine-induced CPP model by i.c.v. injection, but also suggest that the antiepileptic drug VPA may be utilized as potential therapeutic medications for drug abuse in the future.     

Naloxone antagonizes a central histaminergic stimulation of corticosterone secretion in rats

The interaction of central opioid receptors with histaminergic stimulation of the hypothalamo-pituitary-adrenocortical axis, evaluated indirectly through corticosterone secretion, was investigated in conscious unstressed rats. To avoid any possible direct action on the adrenal cortex, all drugs were given intracerebroventricularly (i.c.v.). Histamine, 2-pyridylethylamine (PEA), a histamine H₁-receptor agonist, and 4-methyl-histamine (MeHA) and dimaprit, the H₂-receptor agonists, considerably increased the serum corticosterone levels 1 h after adminstration. Naloxone, an opioid receptor antagonist, almost abolished the corticosterone response to PEA and considerably reduced the responses to MeHA, dimaprit and histamine. The maximum inhibitory effects of naloxone on corticosterone responses induced by histamine and histamine agonists were comparable with those of the H₁-and H₂-receptor antagonists, mepyramine and cimetidine.These results strongly suggest that a major part of the histaminergic stimulation of the hypothalamopituitary-adrenal axis is mediated by central opioid receptorsThe study was supported by the Polish Academy of Sciences, grant No 06.03.     

Putative neuroprotective role of centrally administered corticotropin-releasing factor in low-temperature-exposed neonatal chicks

Corticotropin-releasing factor (CRF) modulates the activity of the hypothalamic–pituitary–adrenal axis, and has a key role in mediating neuroendocrine effects that occur in response to stressful stimuli. We have recently shown that exposure of neonatal chicks to low-temperature resulted in increased oxidative damage to the brain and i.c.v. injection of CRF increased homeothermy that was associated with tissue specific enhancement of mitochondrial fatty acid oxidation enzyme activities. These observations prompted an investigation into the potential role of CRF in a state of oxidative damage in the brain and other vital organs in low-temperature-exposed chicks. In the first experiment, neonatal chicks (Gallus gallus) were given i.c.v. injection of CRF (42 pmol) or saline and were then exposed to low-temperature (20 °C) for 3 h. Malondialdehyde (MDA) levels were measured in the plasma, brain, heart and skeletal muscle. In the second experiment, to confirm the modulatory role of CRF in the brain oxidative damage, as observed in the first experiment, neonatal chicks were given the i.c.v. injection of CRF (42 pmol), astressin (6 nmol, CRF receptor antagonist), or CRF (42 pmol) plus astressin (6 nmol) in combination, and were then exposed to low-temperature (20 °C) for 3 h. CRF significantly decreased the weight gain and feed consumption of chicks that were recovered by astressin. In the plasma, significantly higher MDA levels were observed in i.c.v. CRF chicks exposed to low-temperature, but this pattern was not observed in the brain, heart and skeletal muscle. Brain MDA levels in i.c.v. CRF chicks were decreased as compared with that of i.c.v. saline chicks on low-temperature exposure while i.c.v. astressin increased the MDA levels. In conclusion, CRF plays a putative neuroprotective role in the brain of low-temperature-exposed neonatal chicks.     

Immunodeficiency, growth hormone deficiency and central nervous system involvement in a girl.

We describe a mentally retarded 12-year-old girl with ataxia in whom diagnostic evaluation for short stature revealed isolated growth hormone (GH) deficiency and multiple central nervous system (CNS) lesions. Assessment of immunologic status, performed because of the persistence of recurrent respiratory tract infections, showed associated deficiencies of IgG2-IgG4 and specific antibody response; in addition, in vitro lymphocyte response to mitogens was low, in vitro production of interleukin-2 and of IgM was absent, and natural killer activity was decreased. The possibility that association of the CNS lesions, GH deficiency and immune defects could be due to alterations of the neuro-immuno-endocrine network secondary to a disturbance of neurotransmitters induced by precocious CNS damage of a viral or ischemic nature is discussed.     

Macrophage migration inhibition as a correlate of cell-mediated immunity to herpes simplex virus type 2 in mice

Mice inoculated intraperitoneally or intravenously with herpes simplex virus type 2 (HSV-2) develop a focal necrotizing hepatitis. The livers show expanding foci of necrosis and increasing virus content during the first days of the infection with maximal titers achieved on day 3. The clearance of virus from the organ is manifest from day 4 onward with the most dramatic fall in virus content occurring between days 4 and 5. The development of immunity during the course of infection was assessed by adoptive transfer experiments and by measuring macrophage migration inhibition factor (MIF) production of spleen cells in an indirect agarose microdroplet assay. Antiviral activity of adoptively transferred spleen cells was demonstrable from day 4 of the infection when 50 X 10(6) spleen cells were transferred into recipient mice infected 24 h previously. MIF production in spleen cell cultures stimulated with antigen was found to be specific in that activity was only detected in cultures derived from immune mice and stimulated with the virus antigen. The response was found to be antigen-dose and cell-number dependent. Significant MIF production was demonstrable in spleen cell cultures derived from mice 3 days after the infection, i.e. concomitant with the initiation of recovery and before antiviral activity can be detected in transfer experiments. It is suggested that a delayed type hypersensitivity reaction with lymphokine production leading to recruitment of macrophages and their retention and activation in the foci of infection may be a major factor in the recovery from the infection.     

Clinical applications of growth hormone for ovarian stimulation

The realization of the existence of an intra-ovarian regulatingmechanism involving insulin-like growth factor-I (IGF-I), amediator of growth hormone (GH) action that augments the ovarianresponse to gonado-trophins, has prompted a number of clinicaltrials exploring the use of GH as an adjuvant for ovarian stimulationwith human menopausal gonadotrophin. A critical review of thesestudies pinpoints a select group of infertile patients who maybenefit from this co-treatment, particularly those who havea surgical, pathological or medically induced dysfunction ofGH kinetics. The mechanism of this action, the effective doseneeded and the implications regarding the interface of GH, IGF-Iand ovarian physiology and pathology are now becoming clearer.A greater understanding of GH action on the ovary may in futurebenefit patients afflicted by anovulatory infertility and thoserequiring ovulation induction for in-vitro fertilization.     

Changes in spontaneous and evoked release of transmitter induced by the crotoxin complex and its component phospholipase A2 at the frog neuromuscular junction.

The time course and characteristics of the changes induced by the action of the crotoxin complex and of its component phospholipase A₂ on transmission at the frog neuromuscular junction was studiedin vitro at single endplates using intracellular recording techniques. Both the crotoxin complex and phospholipase A₂ induced variable changes in spontaneous transmitter release in which bursts of miniature endplate potentials alternated with periods when the frequency of miniature endplate potentials was stable but their amplitudes were markedly heterogeneous. The bursts of miniature endplate potentials were of sudden onset and of a high initial frequency, and their duration and incidence were highly variable both at one endplate and between endplates. These changes in the frequency and amplitude of miniature potentials occurred both before and after the abolition of neurally evoked endplate potentials and in the presence of tetrodotoxin. At a late stage in crotoxin intoxication, potassium depolarization of the motor nerve terminals failed to increase spontaneous transmitter release. Both the crotoxin complex and phospholipase A₂ reduced the amplitude of endplate potentials although phospholipase A₂ was less effective. The course of depression of the quantal content of evoked transmitter release induced by the crotoxin complex was occasionally interrupted by a brief facilitation of response; these irregularities in the rate of depression were more clearly seen when endplate potentials were recorded at partially curarized endplates exposed to either the crotoxin complex or to phospholipase A₂. At the stage of abolition of endplate potentials an increase in the external concentration of Ca^{2 +} enabled the evoked response to be restored temporarily. The crotoxin complex and phospholipase A₂ had no effect on the input resistance of the sarcolemmal membrane, but raised the threshold stimulus required to initiate an action potential at concentrations which affected transmitter release. Crotapotin did not affect any of the measured parameters even at high concentrations.The diversity of changes observed in the properties of spontaneous and evoked transmitter release, suggests that the crotoxin complex and phospholipase A₂ may induce two kinds of alterations in the structure of the presynaptic membrane as a result of the action of phospholipase A₂, viz (a) the formation of transient instabilities with an increased Ca^{2 +} inflow and (b) prolonged disturbance of the calcium channel and/or the synchronized release of subunits at the active zone.     

Kinetic analysis of thyrotropin-releasing hormone binding in the central nervous system: evidence for receptor desensitization

To investigate the mechanism(s) of experimentally and clinically observed refractoriness of spinal lower motor neurons (LMNs) to the excitatory effects of high-dose TRH, we examined the kinetics of dissociation of [3H]TRH from its CNS-receptor. At 23 degrees C, the receptor was rapidly (40 min) and completely converted from a form with fast dissociation kinetics (complex I; t1/2 20-30 min) to one from which the peptide dissociated much more slowly (complex II; t1/2 greater than 120 min). This conversion required the presence of added agonist ([3H]TRH) and was not prevented by the GTP-analog Gpp(NH)p. We suggest that complexes I and II may respectively represent active and inactive (desensitized) forms of the TRH-receptor and that TRH-induced I to II conversion of the receptor is responsible for refractoriness of LMNs to the drug.     

Enhancement by BCG of macrophage-like suppressor cells that inhibit the expression of cytotoxic T-cell effector function

The expression of alloimmune splenic T-cell mediated cytotoxicity, as determined by the 51Cr release assay, in animals undergoing allograft rejection, was observed to be inhibited by a cell present in the plastic-adherent fractions of the spleens. The activity of the suppressor cell, induced by the presence of the allograft, was enhanced if the animals were treated with BCG: The latter also potentiated the rejection response. The suppressor cell acted at the cytolytic phase of the effector function so that there was a measurable increase in the response if the suppressor cells were removed from the immune spleens prior to the assay. The cell responsible for the suppressor activity was macrophage-like in its characteristics, being of light density, adherent to glass surfaces, Thy-1-negative and sensitive to the toxic effects of crystalline silica particles.     

Exogenously administered leptin leads to weight loss and increased physical activity in the marsupial Sminthopsis crassicaudata

The adipose tissue derived cytokine leptin, modifies energy balance via effects on both food intake and energy expenditure. It is not clear, however, whether the component of energy expenditure accounted for by voluntary (nonexercise) physical activity is increased in response to leptin. The aim of this study was to investigate the effect of exogenously administered leptin on physical activity in the marsupial Sminthopsis crassicaudata. Body weight, tail width and food intake, were measured daily and physical activity was measured hourly in normal lean S. crassicaudata (n=8) with ad libitum access to standard laboratory diet. After 5 days baseline the animals were divided into two equal groups (n=4), and either human recombinant leptin (2.5 mg/kg) or placebo was administered twice daily intraperitoneally. Approximately 81% of the total daily activity during the baseline period occurred during the nocturnal phase. After 9 days of leptin administration, there were significant decreases in body weight (P<0.001) and fat content (P<0.01), which were not accompanied by a decrease in total energy intake. Overall daily physical activity increased (P=0.028); this effect was confined to the dark phase (P=0.033). We conclude that in lean S. crassicaudata the exogenous administration of human recombinant leptin results in a decrease in adiposity which occurs in the absence of a measurable effect on food intake and is associated with an increase in non-exercise physical activity at least over the duration of this study.     

Regulation by catecholamines of spontaneous growth hormone secretion in the baboon

To gain an increased understanding of the role of central neurotransmitters in the regulation of spontaneous growth hormone (GH) secretion in the primate, we investigated the effects of peripheral intravenous infusion of the alpha-adrenergic receptor-blocking agent, phentolamine (5.0-mg bolus and 1.5 mg . kg-1 . 12 h-1), and the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine (MPT, 300 mg . kg-1 . 24 h-1), on the pattern of GH secretion in five adolescent male baboons. Serum GH concentrations were measured in blood samples taken at 20-min intervals over 12 h (0530-1730) after an overnight fast. In nontreatment control studies, GH secretion exhibited a predictable rhythmic oscillation with a mean period of 5.7 +/- 0.4 (SE) h. Phentolamine significantly decreased the 12-h mean and integrated GH concentrations compared to control values, but the small peaks of GH, which could be distinguished from base-line concentrations in three of the animals, occurred at the same time as during control studies. Whereas alpha-methyl-p-tyrosine slightly reduced serum levels of GH, it significantly increased the GH pulse frequency in the baboons. A two- to fourfold increase in serum prolactin levels occurred in all animals treated with MPT. These findings suggest that alpha-adrenergic pathways play a stimulatory role in maintaining spontaneous daytime GH secretion in the baboon and that one or more catecholamines are involved in the generation of rhythmic GH release.