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Sulfotransferase (ST)-catalyzed sulfation plays an important role in various neuronal functions such as homeostasis of catecholamine neurotransmitters and hormones. Drosophila is a popular model for the study of memory and behavioral manifestations because it is able to mimic the intricate neuroregulation and recognition in humans. However, there has been no evidence indicating that cytosolic ST(s) is(are) present in Drosophila. The aim of this study is to investigate whether or not cytosolic ST(s) is(are) expressed in the Drosophila nervous system. Immunoblot analysis demonstrated the presence of dehydroepiandrosterone (DHEA) ST-like protein in Drosophila brain and a sensitive fluorometric assay revealed its sulfating activity toward DHEA. Immunohistochemical staining demonstrated this DHEA ST-like protein to be abundant in specific neurons as well as in several bundles of nerve fibers in Drosophila. Clarification of a possible link between ST and a neurotransmitter-mediated effect may eventually aid in designing approaches for alleviating neuronal disorders in humans.

Introduction: Pegvisomant use in acromegaly negates the use of GH levels to monitor disease activity. To achieve antagonism, plasma concentrations must be ~1000-fold greater than GH which with the high homology between the peptides makes GH measurement a challenge when pegvisomant is present. Objective: We investigated the effect of pegvisomant on GH measured using commercially available assays. Methods: Pooled serum samples with GH concentrations Results: With baseline GH Conclusion: The presence of pegvisomant resulted in artefactually low measured GH in most assays. We speculate this fall is due to assay antibody-binding pegvisomant, reducing the amount of available antibody to bind actual GH thereby producing less sandwich formation: the ‘high-dose hook’ effect. In most assays, this effect is modest and results in lower GH, but the level of interference makes them unsuitable for studies on the influence of pegvisomant on GH neuroregulation.

Gastrointestinal motility and transport of water and electrolytes play key roles in the pathophysiology of diarrhea upon exposure to enteric parasites. These processes are actively modulated by the enteric nervous system (ENS), which includes efferent, and afferent neurons, as well as interneurons. ENS integrity is essential to the maintenance of homeostatic gut responses. A number of gastrointestinal parasites are known to cause disease by altering the enteric nervous system. The mechanisms remain incompletely understood. Cryptosporidium parvum, Giardia duodenalis (syn. G. intestinalis, G. lamblia), Trypanosoma cruzi, Schistosoma sp and others alter gastrointestinal motility, absorption, or secretion at least in part via effects on the ENS. Recent findings also implicate enteric parasites such as Cryptosporidium parvum and Giardia duodenalis in the development of post-infectious complications such as irritable bowel syndrome, which further underscores their effects on the gut-brain axis. This article critically reviews recent advances and the current state of knowledge on the impact of enteric parasitism on the neural control of gut functions, and provides insights into mechanisms underlying these abnormalities.

Background: Asthma is one of the urgent problems of modern pediatrics, but neuroregulation mechanisms underlying this disease have not been fully disclosed so far. The autonomic interactions assessment in patients with bronchial asthma is important to understand the pathogenesis and prognosis of the disease. Objective: The aim of the study was to investigate features of autonomic response in children with asthma in the period of exacerbation. Methods: The autonomic nervous system (ANS) of 82 children aged 6 to 18 years old with asthma in the period of exacerbation were investigated. The spectral analysis of the heart rate variability and the correlation rhythmography method (skaterography) were used to assess the ANS state. Investigations were carried out at rest and after clinoorthostatic test. Results: Non-respiratory (slow) waves reflecting the degree of activity of humoral and neural canals of heart rate central regulation were dominated at the spectrogram of 72 (87.80%) children experiencing asthma attack; more than half of patients (58.53%) had predominantly very low-frequency component (VLF%) in the range of fluctuation rate that indicated the influence of neurohumoral regulation. A significant increase in vagosympathetic balance coefficient (LF / HF) was recorded after clinoorthostatic test indicating the activation of the sympathetic nervous system. According to the correlation rhythmography data, a considerable scattering of scattergram points was detected in patients in the baseline state that indicated the predominant influence of parasympathetic nervous system. After the clinoorthostatic test, on the contrary, we observed the «tightness» of the scattergram cloud that could indicate sympathicotonia. Conclusion: The imbalance of the autonomic nervous system in the form of activation of the sympathetic and neurohumoral regulation department was found in children with asthma.

Despite the immense advances of medical research there remains a fundamental theoretical deficit regarding how the body is able to maintain its physiological stability. In other words, what is the mechanism which regulates homeostasis and allostasis and/or what is the relationship between genotype and the influence of the environment (phenotype)? Despite the immense amount of publicity given to the huge increases in the occurrence of the most common lifestyle related ailments (e.g. diabetes, obesity, cardiovascular disease, cancers, Alzheimer’s disease, etc) which have occurred in recent years; most people in the world still have relatively normal levels of body weight and remain free from medical problems during their lifetimes, at least until their advancing years when their body is increasingly less able to maintain its normal regulated function. This article considers whether it is now possible to understand the nature, structure and function of this regulatory mechanism in far more detail than has hitherto been possible. This neuroregulatory mechanism involves the influence of light upon brain function and hence upon the autonomic nervous system and physiological systems. There is a particular emphasis in this article upon the regulation of Blood Glucose and how Acidity plays a significant role in diabetes etiology. Finally, the article introduces a Mathematical Model of the Autonomic Nervous System and/or the Physiological Systems (developed by Dr IG Grakov) which has been incorporated into a commercialised technology which is based upon the concepts outlined.

Context: In patients with severe radiation-induced GH deficiency, we previously demonstrated that pulsatile GH secretion and diurnal rhythm are maintained in the fed state, albeit with great attenuation of the pulse amplitude. However, it remained unclear whether stressing the hypothalamic-pituitary axis could unmask neurosecretory dysregulation that is not seen under basal conditions. In addition, the impact of fasting on GH pulsatility and diurnal variation in GHdeficient patients has not been studied in detail before. Study Subjects and Design: Twenty-four-hour GH profiles at 20min intervals were undertaken in the fed state and in the last 24 h of a 33-h fast in eight young adult cancer survivors (two women) with severe GH deficiency after cranial irradiation for nonpituitary brain tumors in childhood and 14 matched normal controls (three women). A sensitive chemiluminescence GH assay was used with cluster analysis. Results: Fasting induced a significant (P 0.05) rise in all amplitude-dependent measures (absolute GH peak and nadir, profile mean GH, and mean pulse amplitude and area) in both groups. Pulse frequency was nonsignificantly increased (by 10%) in normals but significantly increased (by 20%) in the patients. The average increase in the individual fasting profile mean GH concentration was 3.7-fold (range 1.5–8.3) in normals, compared with 2.7-fold (range 1–4.7) in the patients (P 0.05). Fasting amplified amplitude-related differences between patients and controls, and thus, unlike in the fed state, the day (0900–2040 h) mean GH completely demarcated patients from normals. An absolute GH peak level of 2 and 4 g/liter and a profile mean GH level of 0.25 and 0.65 g/liter completely separated patients from normals in the fed and the fasting states, respectively. Overall, fasting seems to induce a feminized pattern of GH secretion with relatively higher interpeak levels, preserved but diminished diurnal variation, and increased secretory disorderliness (increased approximate entropy scores). Conclusion: The overall pulsatile pattern of GH secretion during fasting in patients with radiation-induced GH deficiency and the relative augmentation in GH release are similar to that seen in normals emphasizing that GH neuroregulation is preserved in these patients even when the hypothalamic-pituitary axis is under physiological stress. (J Clin Endocrinol Metab 91: 987–994, 2006)

The hypothalamus-pituitary-adrenal (HPA) axis exerts a variety of effects at both the central and peripheral level. Its activity is mainly regulated by CRH, AVP, and the glucocorticoid-mediated feedback action. Moreover, many neurotransmitters and neuropeptides influence HPA axis activity by acting at the hypothalamic and/or suprahypothalamic level. Among them, GABA and Growth Hormone Secretagogues (GHS)/GHS-receptor systems have been shown to exert a clear inhibitory and stimulatory effect, respectively, on corticotroph secretion. Alprazolam (ALP), a GABA-A receptor agonist, shows the most marked inhibitory effect on both spontaneous and stimulated HPA axis activity, in agreement with its peculiar efficacy in panic disorders and depression where an HPA axis hyperactivation is generally present. Ghrelin and synthetic GHS possess a marked ACTH/cortisol-releasing effect in humans and the ghrelin/GHS-R system is probably involved in the modulation of the HPA response to stress and nutritional/metabolic variations. The glucocorticoid-mediated negative feedback action is mediated by both glucocorticoid (GR) and mineralocorticoid (MR) receptors activation at the central level, mainly in the hippocampus. In agreement with animal studies, MRs seem to play a crucial role in the maintenance of the circadian ACTH and cortisol rhythm, through the modulation of CRH and AVP release. GABA agonists (mainly ALP), ghrelin, as well as MR agonists/antagonists, may represent good tools to explore the activity of the HPA axis in both physiological conditions and pathological states characterized by an impaired control of the corticotroph function.

Exposure to tobacco smoke is a major risk factor for the sudden infant death syndrome. Nicotine is thought to be the ingredient in tobacco smoke that is responsible for a multitude of cardiorespiratory effects during development, and pre- rather than postnatal exposure is considered to be most detrimental. Nicotine interacts with endogenous acetylcholine receptors in the brain and lung, and developmental exposure produces structural changes as well as alterations in neuroregulation. Abnormalities have been described in sympathicovagal balance, arousal threshold and latency, breathing pattern at rest and apnea frequency, ventilatory response to hyperoxia or hypoxia, heart rate regulation and ability to autoresuscitate during severe hypoxia. This review discusses studies performed on infants of smoking mothers and nicotine-exposed animals yielding varying and sometimes inconsistent results that may be due to differences in experimental design, species and the dose of exposure. Taken together however, developmental nicotine exposure appears to induce vulnerability during hypoxia and a potential inability to survive severe asphyxia.

Dynamics of GH secretion in patients with GH deficiency due to radiation damage of the hypothalamic-pituitary (h-p) axis acquired in childhood has rarely been studied. Thus, we used a sensitive chemiluminescence GH assay to analyze 24-h GH profiles (20-min sampling) from 10 adult cancer survivors with severe GH deficiency acquired after brain irradiation in childhood for nonpituitary brain tumors. An age- and sex-matched control group of 30 normal healthy volunteers, eight of whom were matched for body mass index with the patients, were also studied. Cluster analysis with gender-specific comparisons revealed a significant reduction (P < 0.05) in all amplitude-related measurements [profile mean GH levels or area under curve for GH, absolute (maximum) GH peak height, mean peak height, and mean pulse area] in patients. No differences were observed in frequency-related measurements (pulse frequency, pulse duration, and interpulse interval). Pulsatile secretion was relatively more attenuated than basal secretion in patients, and approximate entropy (ApEn) scores were significantly (P < 0.05) elevated, suggesting more disordered GH secretion. Radiation inflicts quantitative damage to the h-p axis, leading to amplitude-dependent dampening of GH secretion with relative preservation of nonpulsatile secretion. Qualitative perturbation in hypothalamic control of GH release is evident by the increase in ApEn values reflecting more disordered GH secretion. The integrity of the h-p axis and GH neuroregulation is fundamentally preserved in irradiated GH-deficient patients with a GH secretory pattern similar to that observed in normal subjects and those with GH deficiency due to other etiologies.

BACKGROUND/AIMS: Orexins (OXs) are a newly described family of hypothalamic neuropeptides. Based on the distribution of OX neurons and their receptors in the brain, it has been postulated that they could play a role in the regulation of neuroendocrine function. GH secretion is markedly influenced by nutritional status and body weight. To investigate the role OX-A plays in the neuroregulation of GH secretion we have studied its effect on spontaneous GH secretion as well as GH responses to GHRH and ghrelin in freely moving rats. Finally, we also assessed the effect of OX-A on in vitro GH secretion. METHODS: We administered OX-A (10 microg, i.c.v.) or vehicle (10 microl, i.c.v.) to freely moving rats. Spontaneous GH secretion was assessed over 6 h with blood samples taken every 15 min. RESULTS: Administration of OX-A led to a decrease in spontaneous GH secretion in comparison with vehicle-treated rats, as assessed by mean GH levels (means+/-s.e.m. 4.2+/-1.7 ng/ml vs 9.4+/-2.2 ng/ml; P

Nitric oxide (NO), a neurotransmitter in autonomic reflex pathways, plays a role in functional neuroregulation of the lower urinary tract. Upregulation of the levels of neuronal nitric oxide synthase (nNOS), the enzyme system responsible for NO synthesis, has been documented in the peripheral, spinal and supraspinal segments of the micturition reflex in diseases such as cystitis, bladder/sphincter dyssynergia following spinal cord injury and bladder overactivity after cerebral infarction. These observations suggest that NO might play a role in the development of bladder overactivity. In this study, nNOS-immunoreactivity (IR) was evaluated in bladder afferent and spinal neurons following bladder outflow obstruction (BOO) in male and female rats. Chronic BOO was induced by placing lumen reducing ligatures around the proximal urethra. Six weeks following the obstructive or sham surgery, bladder function was evaluated by awake cystometry. Bladder afferent neurons in L1, L2, L6 and S1 dorsal root ganglia (DRG) were identified by retrograde neuronal labeling with injection of Fast Blue into the bladder smooth muscle. A differential distribution of nNOS-IR was subsequently evaluated in bladder afferent neurons in the DRG and in the associated spinal cord segments. The percentage of bladder afferent neurons expressing nNOS-IR was increased in L6 (1.8-fold in males and 1.9-fold in females) and S1 (2.8-fold in males and 5.3-fold in females) DRG. In contrast, no changes in nNOS-IR in neurons or fiber distribution were observed in any spinal cord segments examined.

Liver progenitor cells as well as hepatic stellate cells have neuroendocrine features. Progenitor cells express chromogranin-A and neural cell adhesion molecule, parathyroid hormone-related peptide, S-100 protein, neurotrophins, and neurotrophin receptors, while hepatic stellate cells express synaptophysin, glial fibrillary acidic protein, neural cell adhesion molecule, nestin, neurotrophins, and their receptors. This phenotype suggests that these cell types form a neuroendocrine compartment of the liver, which could be under the control of the central nervous system. We recently showed that the parasympathetic nervous system promotes progenitor cell expansion after liver injury, since selective vagotomy reduces the number of progenitor cells after chemical injury in the rat. Similarly, after transplantation, which surgically denervates the liver, human livers that develop hepatitis have fewer progenitor cells than native, fully innervated livers with similar degrees of liver injury. There is also accumulating experimental evidence linking the autonomic system, in particular the sympathetic nervous system (SNS), with the pathogenesis of cirrhosis and its complications. Recently, it has been shown that hepatic stellate cells themselves respond to neurotransmitters. Moreover, inhibition of the SNS reduced fibrosis in carbon tetrachloride-induced liver injury. In view of the denervated state of transplanted livers, it is very important to unravel the neural control mechanisms of regeneration and fibrogenesis. Moreover, since there is a shortage of donor organs, a better understanding of the mechanisms of regeneration could have therapeutic possibilities, which could even obviate the need for orthotopic liver transplantation.

The prevalence of obesity has increased dramatically in recent years in the United States, with similar patterns seen in several other countries. Although there are several potential explanations for this dramatic increase in obesity, dietary influences are a contributing factor. An inverse correlation between dietary sugar intake and body mass index has been reported, suggesting beneficial effects of carbohydrate intake on body mass index. In this review we discuss how sugars interact with regulatory neurochemicals in the brain to affect both energy intake and energy expenditure. These neurochemicals appear to be involved in dietary selection, and sugars and palatable substances affect neurochemical changes in the brain. For example, rats that drink sucrose solutions for 3 wk have major changes in neuronal activity in the limbic area of the brain, a region involved in pleasure and other emotions. We also investigate the relations between sucrose (and other sweet substances), drugs of abuse, and the mesolimbic dopaminergic system. The presence of sucrose in an animal's cage can affect the animals desire to self-administer drugs of abuse. Also, an animal's level of sucrose preference can predict its desire to self-administer cocaine. Such data suggest a relation between sweet taste and drug reward, although the relevance to humans is unclear. Finally, we address the influence of sugar on body weight control. For example, sucrose feeding for 2 wk decreases the efficiency of energy utilization and increases gene expression of uncoupling protein 3 in muscle, suggesting that sucrose may influence uncoupling protein 3 activity and contribute to changes in metabolic efficiency and thus regulation of body weight.

There have been remarkable advances recently in our understanding of the neuroregulation of cough in three areas: the properties of the sensory nerves, in particular their receptors and membrane channels; the plasticity of the pathways; and the central nervous mechanisms of cough. All these studies are relevant to our understanding of the pharmacology and therapy of cough.

Calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed in the peripheral and central nervous system. Demonstrated in the efferent systems of the mammalian cochlea and vestibule, immunoreactive patterns of CGRP may vary by species. There is, however, no information in the literature investigating CGRP localization in the human cochlea. In the present study, the ultrastructural localization of CGRP immunoreactivity was evaluated in the human inner ear with immunoelectron microscopy. It was found that, in human cochlea, CGRP immunoreactivity was located in unmyelinated nerve fibres of the spiral lamina, inner spiral fibres beneath inner hair cells, tunnel spiral fibres, tunnel crossing fibres and outer radial fibres. In endorgans of human vestibule, CGRP immunoreactivity was located in vesiculated nerve fibres and bouton-type nerve terminals which were seen to contact afferent nerve chalices surrounding type I sensory cells and afferent nerve fibres, or to form an en passant contact with afferent dendrites. CGRP immunoreactivity appeared to be confined to efferent systems in all cases. This study presents evidence that CGRP could serve a role in neurotransmission or neuroregulation in both cochlear and vestibular efferent systems of human.

Summary introduction The present clinical investigation uses a high-precision GH immunofluorometric assay to examine the postulate that principally the amplitude mode of GH secretory control is disrupted in adults with GH deficiency. patients and methods To this end, we investigated GH secretory dynamics in a cohort of 19 adult GH-deficient (GHD) patients and 19 age-, gender- and body mass index-matched controls. GHD was established by blunted (

Neuroregulation represented by Neurofeedback (NFB) also called EEG-biofeedback, has been known as a potential therapeutic modality since 1960’s. This type of biofeedback uses real-time displays of EEG to illustrate brain activity and teach self-regulation. Initially, simple systems utilizing one or two EEG sensors were used but many good clinical outcomes required more than 50 sessions. In the 1990s, a new form of EEG biofeedback (Z-score biofeedback) was suggested, in which real-time comparisons to an age matched reference population of healthy or normal subjects were used as a guide to increase specificity and provide a uniform direction and threshold for the biofeedback process [1].

Apolipoprotein E (ApoE) gene and primarily its allele e4 have been identified as a risk factor for Alzheimer's disease (AD). The prevalence of the gene in 25-30% in the population makes it essential to estimate its role in neuroregulation and its impact on distributed brain networks. In this study, we provide computational neuroanatomy based interpretation of large-scale and small-world cortical networks in cognitive normal (CN) subjects with differing Apolipoprotein-E4 (ApoE4) gene expression. We estimated large-scale anatomical networks from cortical thickness measurements derived from magnetic resonance imaging in 147 CN subjects explored in relation to ApoE4 genotype (e4+ carriers (n=41) versus e4- non-carriers (n=106)). Brain networks were constructed by thresholding cortical thickness correlation matrices of 68 bilateral regions of the brain analyzed using well-established graph theoretical approaches. Compared to ApoE4 non-carriers, carriers showed increased interregional correlation coefficients in regions like precentral, superior frontal and inferior temporal regions. Interestingly most of the altered connections were intra-hemispheric limited primarily to the right hemisphere. Furthermore, ApoE4 carriers demonstrated abnormal small-world architecture in the cortical networks with increased clustering coefficient and path lengths as compared to non-carrier, suggesting a less optimal topological organization. Additionally non-carriers demonstrated higher betweenness in regions such as middle temporal, para-hippocampal gyrus, posterior cingulate and insula of the default mode network (DMN), also seen in subjects with AD and mild cognitive impairment (MCI). The results suggest that the complex morphological cortical connectivity patterns are altered in ApoE4 carriers as compared to non-carriers, providing evidence for disruption of integrity in large-scale anatomical brain networks.

Capsaicin, the pungent ingredient of red pepper has become not only a “hot” topic in neuroscience but its new target-related unique actions have opened the door for the drug industry to introduce a new chapter of analgesics. After several lines of translational efforts with over 1,000 patents and clinical trials, the 8 % capsaicin dermal patch reached the market and its long-lasting local analgesic effect in some severe neuropathic pain states is now well established. This introductory chapter outlines on one hand the historical background based on the author’s 50 years of experience in this field and on the other hand emphasizes new scopes, fascinating perspectives in pharmaco-physiology, and molecular pharmacology of nociceptive sensory neurons. Evidence for the effect of capsaicin on C-polymodal nociceptors (CMH), C-mechanoinsensitive (CHMi), and silent C-nociceptors are listed and the features of the capsaicin-induced blocking effects of nociceptors are demonstrated. Common and different characteristics of nociceptor-blocking actions after systemic, perineural, local, intrathecal, and in vitro treatments are summarized. Evidence for the misleading conclusions drawn from neonatal capsaicin pretreatment is presented. Perspectives opened from cloning the capsaicin receptor “Transient Receptor Potential Vanilloid 1’’ (TRPV1) are outlined and potential molecular mechanisms behind the long-lasting functional, ultrastructural, and nerve terminal-damaging effects of capsaicin and other TRPV1 agonists are summarized. Neurogenic inflammation and the long-list of “capsaicin-sensitive” tissue responses are mediated by an unorthodox dual sensory-efferent function of peptidergic TRPV1-expressing nerve terminals which differ from the classical efferent and sensory nerve endings that have a unidirectional role in neuroregulation. Thermoregulatory effects of capsaicin are discussed in detail. It is suggested that since hyperthermia and burn risk due to enhanced noxious heat threshold are the major obstacles of some TRPV1 antagonists, they could be overcome. The special “multisteric” gating function of the TRPV1 cation channel provides the structural ground for blocking chemical activation of TRPV1 without affecting its responsiveness to physical stimuli. A new chapter of potential analgesics targeting nociceptors is now already supported for pain relief in persistent pathological pain states.

This chapter reviews current literature on hormonal and neural signals critical for the regulation of individual meals and body fat. Body weight is regulated via an ongoing process called energy homeostasis, or the long-term matching of food intake to energy expenditure. Reductions from an individual’s “normal” weight due to lack of sufficient food lowers levels of adiposity signals (leptin and insulin) reaching the brain from the blood, activates anabolic hormones that stimulate food intake, and decreases the efficacy of meal-generated signals (such as cholecystokinin or CCK) that normally reduce meal size. A converse sequence of events happens when individuals gain weight, adiposity signals are increased, catabolic hormones are stimulated, and the consequence is a reduction in food intake and a normalization of body weight. The brain also functions as a “fuel sensor” and thereby senses nutrients and generates signals and activation of neuronal systems and circuits that regulate energy homeostasis. This chapter focuses on how these signals are received and integrated by the central nervous system (CNS).

Although a critical mass of adipose tissue is essential for the normal development of female reproductive function, obesity has been shown to produce menstrual disturbances and subfertility. The severity of obesity and the distribution of fat tissue are important factors that influence the female reproductive system. The pathogenetic mechanistic links between them aren't clearly elucidated. Obese women, especially those with upper body obesity, have insulin resistance and hyperinsulinaemia, hyperandrogenaemia, increased peripheral aromatization of androgens to oestrogens, altered gonadotrophin secretion, decreased sex hormone binding globulin, decreased growth hormone (GH) and insulin like growth factor binding proteins (IGFBPs), increased leptin levels and altered neuroregulation of the hypothalamic-pituitary-gonadal axis. These have been considered as some of the links in the sequence of events of the disrupted ovulatory process. The mechanisms of these actions and their influence on female reproductive function are discussed below.

Amenorrheic athletes exhibit a spectrum of neuroendocrine disturbances, including alterations in the GH-insulin-like growth factor I (IGF-I) axis. Whether these changes are due to exercise or amenorrhea is incompletely characterized. The present study investigates spontaneous (overnight) and exercise-stimulated GH secretion and associated IGF-binding proteins (IGFBPs) in amenorrheic (AA; n = 5), and eumenorrheic athletes ( n = 5) matched for age, percent body fat (dual energy x-ray absorptiometry), training history, and maximal oxygen consumption. Each volunteer participated in two hospital admissions consisting of a 50-min submaximal exercise bout (70% maximal oxygen consumption) and an 8-h nocturnal sampling period. Deconvolution analysis of serum GH concentration time series revealed increases in the half-life of GH (60%) and the number of secretory bursts (85%) as well as a decrease in their half-duration (50%) and the mass of GH secreted per pulse (300%) in the AA cohort. Time occupancy at elevated trough GH concentrations was significantly increased, and GH pulsatility (approximate entropy) was more irregular in the AA group. During exercise, AA exhibited a reversal of the normal relationship between IGF-I and GH, and a 4- to 5-fold blunting of stimulated peak and integrated GH secretion. Fasting levels of plasma IGF-I, IGFBP-3, and IGFBP-1 appeared to be unaffected by menstrual status. In ensemble, this phenotype of GH release in amenorrheic athletes suggests disrupted neuroregulation of episodic GH secretion, possibly reflecting decreased somatostinergic inhibition basally, and reduced GHRH output in response to exercise compared with eumenorrheic athletes. Accordingly, we postulate that the amenorrheic state, beyond the exercise experience per se, alters the neuroendocrine control of GH output in amenorrheic athletes.

Spiritual life is made possible by the evolution of a human neuropsychology that requires social interdependence for its development. Extensive neuroplasticity requires experiential shaping throughout life. The evolution of frontal cortex hypertrophy suggests that much of this shaping is produced by a socially constructed virtual reality, extending beyond immediate experience. Prefrontal colonization makes possible the social scaffolding of neuroregulation, including the emotional attachments necessary for moral life. Cognitive independence from immediate environments enables symbioses with external memory systems, producing novel forms of socially constituted experience and making possible the transformative effect of religious systems upon individual biologies and psychologies.

Growth hormone (GH) is essential for postnatal somatic growth, maintenance of lean tissue at maturity in domestic animals and milk production in cows. This review focuses on neuroregulation of GH secretion in domestic animals. Two hormones principally regulate the secretion of GH: growth hormone-releasing hormone (GHRH) stimulates, while somatostatin (SS) inhibits the secretion of GH. A long-standing hypothesis proposes that alternate secretion of GHRH and SS regulate episodic secretion of GH. However, measurement of GHRH and SS in hypophysial-portal blood of unanesthetized sheep and swine shows that episodic secretion of GHRH and SS do not account for all episodes of GH secreted. Furthermore, the activity of GHRH and SS neurons decreases after steers have eaten a meal offered for a 2-h period each day (meal-feeding) and this corresponds with reduced secretion of GH. Together, these data suggest that other factors also regulate the secretion of GH. Several neurotransmitters have been implicated in this regard. Thyrotropin-releasing hormone, serotonin and gamma-aminobutyric acid stimulate the secretion of GH at somatotropes. Growth hormone releasing peptide-6 overcomes feeding-induced refractoriness of somatotropes to GHRH and stimulates the secretion of GHRH. Norepinephrine reduces the activity of SS neurons and stimulates the secretion of GHRH via alpha(2)-adrenergic receptors. N-methyl-D,L-aspartate and leptin stimulate the secretion of GHRH, while neuropeptide Y stimulates the secretion of GHRH and SS. Activation of muscarinic receptors decreases the secretion of SS. Dopamine stimulates the secretion of SS via D1 receptors and inhibits the secretion of GH from somatotropes via D2 receptors. Thus, many neuroendocrine factors regulate the secretion of GH in livestock via altering secretion of GHRH and/or SS, communicating between GHRH and SS neurons, or acting independently at somatotropes to coordinate the secretion of GH.

Neuromodulation in the bioelectrical domain is an attractive option for the remediation of functionally based deficits. Most of the interest to date has focused on exogenous methods, such as repetitive transcranial magnetic stimulation, transient direct current stimulation, vagus nerve stimulation, and deep brain stimulation. Much less attention has been given to endogenous methods of exploiting latent brain plasticity. These have reached a level of sophistication and maturity that invites attention. Over the last 7 years, the domain of infralow frequencies has been exploited productively for the enhancement of neuroregulation. The principal mechanism is putatively the renormalization of functional connectivity of our resting-state networks. The endogeneous techniques are particularly attractive for the pediatric population, where they can be utilized before dysfunctional patterns of brain behavior become consolidated and further elaborated into clinical syndromes.

Physical exercise is an important physiological stimulus to growth hormone (GH) release in man. Many neurotransmitters are involved in GH regulation. We studied the effect of the cholinergic pathway on GH secretion induced by physical exercise. Particularly, we studied the effect of a cholinergic muscarinic agonist on GH-induced physical exercise, both in children and adults. Moreover, we investigated the refractoriness of GH secretion after a second physical exercise stimulus. Three different protocols were performed: 1) GH response to physical exercise in children and adults; 2) effect of pyridostigmine on exercise-induced GH secretion in children and adults; 3) GH response to two consecutive exercises in children and adults. Our data show that in children GH peak after physical exercise is higher than in adults. Pyridostigmine enhances GH release in children and in adults. Exercise stimulus was able to release GH in the second test only in children, while the refractory phase did not permit a new GH release in adults. The shift to a modality of neural control of GH secretion peculiar of adults is likely due to neuroregulatory mechanisms which may be partly dependent on long-term variation in hormonal milieu.

A general approach to non-stationary data from a non-linear dynamical time series is presented. As an application, the RR intervals extracted from the 24 h electrocardiograms of 60 healthy individuals 16–64 yr of age are analyzed with the use of a sliding time window of 100 intervals. This procedure maps the original time series into a time series of the given complexity measure. The state of the system is then given by the properties of the distribution of the complexity measure. The relation of the complexity measures to the level of the catecholamine hormones in the plasma, their dependence on the age of the subject, their mutual correlation and the results of surrogate data tests are discussed. Two different approaches to analyzing complexity are used: pattern entropy as a measure of statistical order and algorithmic complexity as a measure sequential order in heart rate variability. These two complexity measures are found to reflect different aspects of the neuroregulation of the heart. Finally, in some subjects (usually younger persons) the two complexity measures depend on their age while in others (mostly older subjects) they do not – in which case the correlation between is lost.

To appraise the neuroendocrine mechanisms that underlie a selective (monotropic) elevation of serum FSH concentrations in healthy older men, we sampled blood in 11 young (ages 21–34) and 8 older men (ages 62–72) men every 2.5 min overnight. Serum FSH concentrations were quantitated in an automated, high-sensitivity, chemiluminescence-based assay. Rates of basal and pulsatile FSH secretion were estimated by deconvolution analysis, and the orderliness of the FSH release process via quantitated the approximate entropy statistic. Statistical analysis revealed that healthy older men manifest dual neuroendocrine hypersecretory mechanisims; specifically, a 2-fold increase in the basel (nonpulsatile) FSH secretion rate, and a concurrent 50% amplification of FSH secretory burst mass (and amplitude). The regularity or orderliness of ad seriatim FSH release is preserved in older individuals. We postulate that higher basel FSH secretion in older men is a consequence of reduced testosterone negative feedback, whereas amplified FSH secretory burst mass reflects net enhanced stimulation of gonadotrope cells by endogenous FSH secretagogues (e.g. GnRH and/or activin). The foregoing specific mechanisms driving heightened FSH secretion in older men contrast with the lower-amplitude pulsatility and more disorderly patterns of LH release in the same individuals. Thus, the present data illuminate an age-dependent disparity in the disruption of FSH neuroregulation in the aging male.

This review focuses on studies that pertain to obesity and aging. The prevalence of obesity in the elderly is discussed, with an emphasis on body-fat distribution as it relates to morbidity and mortality rates. Treatment options, such as physical activity, growth hormones, and drug therapy, are briefly mentioned. A section that covers some of the most recent issues pertaining to the neuroregulation of feeding and energy expenditure is included. Finally, we briefly discuss anorexia in the aged.

Neurotransmitter transporters are involved in termination of the synaptic neurotransmission and they also play a key role in neuroregulation and brain development. In this report, we describe the developmental distribution of the y-aminobutyric acid transporter GAT3 which transports gamma-aminobutyric acid (GABA) and beta-alanine in a sodium chloride-dependent manner. GAT3 was localized to the meninges in developmental stages where two other GABA transporters, GAT1 and GAT4, were adjacently expressed. In later developmental stages, only GAT3 remained in this area. The expression of GAT3 in the peripheral embryonic tissues was confined to the liver, to a layer of cells under the skin, to the mouse kidney, and to hipoccampal blood vessels only in late developmental stages. The developmental distribution of GAT3 suggests involvement in central nervous system (CNS) maturation.

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

The purpose of this study was to elucidate the neuroregulation of sphincteric relaxation by investigating the density of nerves containing acetylcholine, noradrenaline, neuropeptide Y (NPY), galanin, vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP) in the urethral sphincter in patients without a voiding disorder. The complete urethral sphincter (from the bladder neck to beyond the striated external sphincter) was excised from four male and four female adult cadavers and one male and one female fetus. In transverse paraffin or cryostat sections, the above transmitters were identified by histochemical methods. The striated sphincter was densely innervated by cholinergic nerves. Adrenergic nerves next to striated fibers were rare, but were present in all patients. NPY was seen rarely along striated fibers. In the smooth sphincteric component, noradrenaline-, acetylcholine-, NPY- and galanin-reactive nerves were observed frequently. Only functional studies can clarify the clinical implications of these results. Judging from NPY's scarcity in the striated sphincter no efferent function is anticipated. In the smooth component the frequent appearance of NPY, galanin and noradrenaline suggests a regulatory role for these transmitters.

We studied the neural regulation of seminal vesicles (SV) by determining the changes of intraluminal pressure of rat SV in response to an electric stimulation of the lesser splanchnic nerve (LSN). After pharmacological manipulation with neurotoxin, the contents of monoamines and their metabolites in SV were estimated. In rats receiving electric stimulation of the LSN, an increase of intraluminal pressure was obtained with a reduction of the serotonergic turnover rate in SV. An intraperitoneal injection of DSP-4 (100 mg/kg), the noradrenergic neurotoxin, into rats decreased the level of norepinephrine (NE) in SV significantly but did not influence this functional response. Also, the intraluminal pressure was lowered by an intrathecal injection of 6-OHDA (20 microg/rat) to denervate spinal monoaminergic nerves in rats although the contents of monoamines in SV were not changed. This indicates that noradrenergic neurotransmission appears unimportant in this regulation. The lowering of intraluminal pressure in rats by 6-OHDA is mainly related to an attenuation of dopaminergic neuroregulation from the decrease of turnover rate of DA. Otherwise, an intrathecal injection of 5,7-DHT (60 microg/rat) to abolish spinal serotonergic nerves did not influence the level of monoamines in SV but increased the intraluminal pressure indicating an involvement of inhibitory regulation from spinal serotonergic pathway. These results suggest that contraction by electric stimulation of the LSN in Wistar rat SV is mainly regulated by the dopaminergic nervous pathway and an inhibitory regulation of the serotonergic nervous pathway from spinal cord while the noradrenergic nervous system seems unimportant for this regulation.

Several abnormalities in neuroendocrine function have been reported in patients with major depression, including dysregulation in prolactin secretion, often in response to a specific pharmacologic stimulus. Because the physiologic and neurochemical regulation of prolactin secretion is complex and only partly elucidated, it is clear that some of the monoamine neurotransmitters that have been implicated in the pathophysiology of depression, in particular serotonin (5-HT), are involved in regulating its release. Prolactin may provide us with a window to the brain , by allowing us to test, albeit indirectly, hypotheses regarding the biochemical basis of depressive illness. To appreciate the significance of studies of prolactin in depression, one needs to understand the psychobiology of the regulation of prolactin release. The authors briefly summarize the neuroregulation of prolactin release, with special emphasis on 5–HT and the influence of 5–HT receptor subtypes on prolactin secretion. They then review the clinical studies of prolactin regulation in depression, including investigations of prolactin rhythms in depression and the prolactin response to neuroendocrine challenge tests.

1. Opioid agonists inhibit neurogenic mucus secretion in the airways. The mechanism of the inhibition is unknown but may be via opening of potassium (K+) channels. We studied the effect on neurogenic secretion in ferret trachea in vitro of the OP1 receptor (formerly known as delta opioid receptor) agonist [D-Pen2,5]enkephalin (DPDPE), the OP2 receptor (formely kappa) agonist U-50,488H, the OP3 receptor (formerly micro) agonist [D-Ala2, N-Me-Phe, Gly-ol5]enkephalin (DAMGO), the ATP-sensitive K+ (K(ATP)) channel inhibitor glibenclamide, the large conductance calcium activated K+ (BK(Ca)) channel blocker iberiotoxin, the small conductance K(Ca) (SK(Ca)) channel blocker apamin, the K(ATP) channel opener levcromakalim, a putative K(ATP) channel opener RS 91309, and the BK(Ca) channel opener NS 1619. Secretion was quantified by use of 35SO4 as a mucus marker. 2. Electrical stimulation increased tracheal secretion by up to 40 fold above sham-stimulated levels. DAMGO or DPDPE (10 microm each) significantly inhibited neurogenic secretion by 85% and 77%, respectively, effects which were reversed by naloxone. U-50,488H had no significant inhibitory effect on neurogenic secretion, and none of the opioids had any effect on ACh-induced or [Sar9]substance P-induced secretion. 3. Inhibition of neurogenic secretion by DAMGO or DPDPE was reversed by iberiotoxin (3 microM) but not by either glibenclamide or apamin (0.1 microM each). Iberiotoxin alone did not affect the neurogenic secretory response. 4. Levcromakalim, RS 91309 or NS 1619 (3 nM-3 microM) inhibited neurogenic secretion with maximal inhibitions at 3 microM of 68%, 72% and 96%, respectively. Neither levcromakalim nor RS 91309 at any concentration tested significantly inhibited acetylcholine (ACh)-induced secretion, whereas inhibition (60%) was achieved at the highest concentration of NS 1619, a response which was blocked by iberiotoxin. 5. Inhibition of neurogenic secretion by levcromakalim (3 microM) or RS 91309 (30 nM) was inhibited by glibenclamide but not by iberiotoxin. In contrast, inhibition by NS 1619 (30 nM and 3 microM) was blocked by iberiotoxin but not by glibenclamide. 6. We conclude that, in ferret trachea in vitro, OP1 or OP3 opioid receptors inhibit neurogenic mucus secretion at a prejunctional site and that the mechanism of the inhibition is via opening of BK(Ca) channels. Direct opening of BK(Ca) channels or K(ATP) channels also inhibits neurogenic mucus secretion. In addition, opening of BK(Ca) channels inhibits ACh-evoked secretion of mucus. Drugs which open BK(Ca) channels may have therapeutic anti-secretory activity in bronchial diseases in which neurogenic mechanisms and mucus hypersecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.

Although the effects of inhibin on gonadotropin synthesis and secretion have been extensively studied, the role of inhibin in the neuroregulation of in vivo growth hormone (GH) secretion still remains to be elucidated. In the present work, we investigated the effects of inhibin on spontaneous GH secretion in three different groups of conscious adult male rats: intact, gonadectomized, and dihydrotestosterone (DHT)-treated gonadectomized animals. We found that inhibin administration (100 µg/kg, i.v.) led to a marked suppression in spontaneous GH secretion in all the groups studied. This significant decrease was assessed by the area under the curve in intact (311.1 ± 163.3 vs. 3,882.1 ± 1,084.6 ng/ml/6 h, p < 0.01), gonadectomized (416.6 ± 120.9 vs. 2,078.5 ± 298.4 ng/ml/6 h, p < 0.01) and gondadectomized rats treated with DHT (755.0 ± 102.3 vs. 4,539.3 ± 1,670.6 ng/ml/6 h, p < 0.01). Furthermore, intravenous inhibin significantly reduced in vivo GH responses to GHRH (10 µg/kg, i.v.) in both intact and gonadectomized rats. These findings suggest a role of inhibin on in vivo GH secretion in the male rat.

The distribution of neuropeptide Y (NPY)-like immunoreactivity in the brain of the bichir, Polypterus senegalus, was examined immunohistochemically. NPY-like immunoreactivity was distributed widely in the brain, with the highest density in the diencephalon. NPY-positive perikarya were found in various areas, including the terminal nerve, the pallial zones of the telencephalon, the periventricular preoptic nucleus, the thalamic nucleus, the ventral hypothalamus of the diencephalon, the tegmentum of the mesencephalon, and the area intermedioventralis of the rhombencephalon. In the hypothalamus, NPY-positive liquor-contacting neurons were frequently observed. Immunoreactive neuron-like cells also appeared in the distal lobe of the hypophysis. NPY fibers were densely distributed in the ventral telencephalon, the hypothalamus, and the ventrolateral area of the rhombencephalon. They were also demonstrated in the terminal nerve. In the hypophysis, NPY fibers were dense in the median eminence, but sparse in the neural lobe. Electron-microscopic double immunostaining of the terminal nerve revealed the coexistence of NPY-like antigen with gonadotropin-releasing hormone-like and molluscan cardioexcitatory tetrapeptide-like antigens in the same cytoplasmic granules. These results suggest that NPY or a related substance is involved in neuroregulation of various areas of the bichir brain, by mainly acting as a neurotransmitter or neuromodulator.

Studies performed in animals and humans have suggested a functional interaction between opioid and cholinergic systems in the control of growth hormone (GH) secretion. Moreover, the sex-dependent modulation of GH secretion in humans is well established. To investigate the role of sex and food intake in the regulation of the reciprocal influences of opioids and acetylcholine in the modulation of GH secretion, we studied the GH response to pyridostigmine (PYR) alone and during a naloxone (NAL) infusion in a group of normal men and women before a meal (at 1:00 PM) and postprandially. In women, the response of GH to PYR alone before the meal was significantly lower than in the men (area under the curve [AUC], mean +/- SEM, 320.18 +/- 87.16 v 1,031.06 +/- 333.21 micrograms/L/90 min, P < .01). Before the meal, NAL completely abolished the response of GH to PYR in men (AUC, 1,031.06 +/- 333.21 v 16.50 +/- 7.50 micrograms/L/90 min, P < .01), whereas infusion of NAL did not significantly modify the GH response to PYR in women. Consumption of the meal significantly decreased PYR-induced GH release in both women (AUC, 21.75 +/- 12.75 v 320.18 +/- 87.16 micrograms/L/90 min, P < .05) and men (AUC, 45.75 +/- 18.75 v 1,031.06 +/- 333.21 micrograms/L/90 min, P < .01). Conversely, food intake did not change the effects of NAL infusion on the GH response to PYR either in women or in men. We conclude that the sex-dependent opioid modulation of PYR-induced GH secretion is observed before a meal but not in the postprandial state. Food intake may be hypothesized to influence the cholinergic regulation of GH secretion and the sex-dependent opioid modulation of central cholinergic tone.

A in deep review of neurotransmitter regulation of gH release in the sheep, an important experimental model for the study of hypophiseal portal blood.

We thank Professor Szolcsanyi for carefully reading our review and for his insightful comment about neuroregulation of the cutaneous microcirculation. We acknowledge that the figure schematizing the pathways underlying local thermal hyperemia in the skin may be partly inaccurate. However, we would like to emphasize that neuroregulation of the initial rise in skin blood flow following local heating remains a rather ‘grey’ area. This initial vasodilation has been commonly (improperly?) referred to as initial ‘axon reflex’ since the pivotal work by Minson and colleagues, who showed that antebrachial cutaneous nerve block with bupivacaine before local heating does not alter the response, whereas application of lidocaine/prilocaine cream reduces the peak amplitude by more than half [1].

Pituitary adenylate cyclase activating peptide (PACAP) is a novel vasoactive intestinal polypeptide-like peptide which is present in neuronal elements of a number of peripheral organs. PACAP occurs in two forms, PACAP-27 and the C-terminally extended PACAP-38, both derived from the same precursor which in addition gives rise to a structurally-related peptide, PACAP-related peptide. Using specific radioimmunoassays for PACAP-38, PACAP-27 and PACAP-related peptide we found that the three PACAP-precursor-derived peptides were present in tissue extracts from all regions of the rat female genital tract. PACAP-38 was the dominating peptide with the highest concentrations in the Fallopian tube and the ovary. Upon reverse phase high pressure liquid chromatography the immunoreactive material was found to co-elute with synthetic PACAP-38, PACAP-27 and PACAP-related peptide, respectively. By immunohistochemistry, PACAP was shown to be located in varicose nerve fibres associated with blood vessels, smooth muscle and epithelial cells. Within the local paracervical ganglion PACAP-immunoreactive fibres ramified often forming varicose, pericellular plexuses around non-PACAP-positive cell bodies. Also bundles of PACAP-immunoreactive fibres were transversing the ganglion. In the paracervical ganglion of normal rat only a few neuronal cell bodies showed immunostaining for PACAP, but after local colchichine-treatment a moderate number of positive perikarya appeared. The synthesis of PACAP in neurons of the paracervical ganglia was confirmed by in situ hybridization histochemistry with a digoxigenin-labelled cRNA probe. Double immunostaining for PACAP and vasoactive intestinal polypeptide disclosed a partial co-existence of the two peptides in nerve fibres of all tubular organs in the rat female genital tract and in cell bodies and nerve fibres in the paracervical ganglion. After neonatal capsaicin treatment the concentration of immunoreactive PACAP-38 as well as the number and intensity of PACAP-positive nerve fibres were reduced while vasoactive intestinal polypeptide immunoreactivity was unaffected. In conclusion, PACAP-immunoreactive nerve fibres have been demonstrated in all regions of the rat female genital tract associated with blood vessels, smooth musculature and epithelium. In some fibres, which seem to originate in the local paracervical ganglia, PACAP was co-localized with vasoactive intestinal polypeptide. PACAP released from these fibres could alone or in concert with vasoactive intestinal polypeptide play a role in neuroregulation of female reproductive organs acting directly on the musculature and vasculature. Other PACAP-containing fibres are sensory in nature, and some of these might influence ganglionic neurotransmission in the local paracervical ganglia.

This review examines possible relationships between anorexia, dietary intake and central nervous system histaminergic activity. The hypothesis being reviewed is that one component of normal or pathophysiological neuroregulation of food intake involves histaminergic activity in the central nervous system, as influenced by concentrations and bioperiodicities of histamine and/or histamine receptors. Changes in concentrations of receptors are gender specific. Low protein quality or quantity diets elevate both central histamine and histamine receptors (H1) in rats while significantly decreasing their food intake. When injected with histaminergic antagonists, rats fed low protein diets increase food intake and have improved efficiency of weight gain. This review supports a dual hypotheses: central histaminergic activity is involved in the regulation of food intake, but food intake patterns (including dietary composition or energy content) can modify central histaminergic activity. This review also suggests that modified histamine and/or H1 receptor concentrations are potential mechanisms for elevated central histaminergic activity in food intake-related pathophysiological states. Thus, dietary interventions (clinically- or self-imposed) which modify food intake or diet composition have the potential of affecting the histaminergic system. Also, drugs with antihistaminergic properties have the potential of affecting food intake/weight gain patterns by interfering with normal neurochemical signals.

The vascular beds, submucosal glands, and airway vasculature are the three primary effector tissues in the airways, and all are under the control of the parasympathetic (vagal) and sympathetic nervous systems. Parasympathetic nerves play a more important role in smooth muscle contraction and gland secretion. The complex neurogenic mechanisms initiated by activation of sensory nerves have been clarified to a large extent by studies on experimental animals. For example, inflammation or an allergic response will cause neurogenic inflammation due to axon reflexes; central nervous reflexes will modulate activity in all of the effector tissues; and these reflex responses will be modulated by local reflexes via parasympathetic ganglia. Similar mechanisms are suspected in humans, but their importance still needs to be fully established.

The growth hormone (GH) secretory pattern is dependent on sex and developmental stage. It is generally accepted that in the male rat this pattern is markedly influenced by androgens secreted by the Leydig cells. Recent findings, however, point to the existence of other non-androgenic testicular factors produced by the Sertoli cells and which regulate in vivo the GH responses to growth hormone releasing hormone (GHRH). The aim of this work was to investigate the role played by non-androgenic testicular factors on hypothalamic somatostatin (SST) and GHRH mRNA levels. Seventy-day-old male Sprague-Dawley rats were used throughout the work. They were divided into five groups: (1) control rats; (2) gonadectomized rats; (3) gonadectomized rats supplemented with exogenous administration of dihydrotestosterone (DHT); (4) ethylene dimethane sulphonate (EDS)-treated rats; (5) EDS-treated rats supplemented with exogenous administration of DHT. EDS is a cytotoxic agent that specifically destroys the Leydig cells. The rats were killed after 15 days of treatment. Hypothalamic SST mRNA levels were determined by Northern blot and by in situ hybridization, and GHRH mRNA levels assessed by Northern blot. We found that selective removal of Leydig cells with EDS greatly reduced the SST mRNA content in the periventricular nucleus of the hypothalamus. These levels were significantly lower than those found in gonadectomized rats. Furthermore, replacement treatment with dihydrotesterone (DHT) did not completely restore SST mRNA levels in EDS-treated rats, contrasting with the complete recovery of SST mRNA levels in gonadectomized rats. On the other hand, gonadectomy and EDS treatment produced a significant reduction in GHRH mRNA levels. DHT administration reversed the action of gonadectomy, but did not restore GHRH mRNA content in EDS-treated rats. These data suggest that, in addition to testosterone, as yet unidentified non-androgenic testicular factors can significantly influence SST and GHRH mRNA levels. This may indicate that non-androgenic testicular factors acting at hypothalamic level may be important in the neuroregulation of GH secretion and in the maintenance of sexual dimorphism in GH secretory pattern.

Summary OBJECTIVE We wished to study alterations in serum insulin-like growth factor-l (IGF-I) and its binding proteins in subjects with insulin dependent diabetes mellitus (IDDM) and possible relations with metabolic and GH secretory status, before and after cholinergic modulation. In addition, we have investigated whether cholinergic modulation exerts any effects on IGF-I secretion, independently of any actions on GH secretory status. DESIGN All subjects received GH releasing hormone (GHRH) 1-44; 80 pg i.v.) alone and 60 minutes following 120 mg of pyridostigmine orally or 200 rng of pirenzepine orally. The three tests were carried out in random order at least one week apart. Blood was sampled at 1Cminute intervals over 120 minutes. PATIENTS Twelve male subjects with IDDM and no clinical evidence of complications were selected on the basis of HbA, levels to provide a wide range of metabolic control. Six normal male subjects were also studied. MEASUREMENTS Serum IGF-I, IGF-binding protein 1 (IGFBP-1) and IGFBP-3 were measured at regular intervals throughout the study. Fasting plasma glucose and HbA, were measured before each study to provide measures of metabolic control. RESULTS Serum IGF-I and IGFBP-3 levels were significantly lower while serum IGFBP-I levels were significantly higher in the diabetic subjects. Pirenzepine had no effect on serum IGF-I, IGFBP-1 or IGFBP-3 in diabetic subjects but caused a significant increase in serum IGF-I and IGFBP-3 levels in normal subjects. between GH responses to GHRH alone or after pirenzepine or pyridostigmine pretreatment and serum levels of IGF-I, IGFBP-1 or IGFBP-3. CONCLUSION These data confirm that subjects with IDDM have reduced serum IGF-I and IGFBP-3 and increased IGFBP-1 levels, the latter being directly related to the fasting plasma glucose concentrations. The absence of any relation between changes in the IGF-I system and altered GH neuroregulation after cholinergic modulation suggests that changes in IGF-I are not the sole contributors to the altered GH neuroregulation which occurs in IDDM. We have also shown an acute stirnulatory effect of pirenzepine on serum IGF-I and IGFBP-3 in normal subjects which is not present in IDDM although the underlying mechanism is unknown.

Neurotransmitter impairments in MDI can also affect hormonal neuroregulation. Therefore, we decided to study the integrated concentration of growth hormone (IC-GH) and its 24-h secretory profile in this pathology. Ten women with major depressive illness (MDI) (three premenopausal and seven postmenopausal) and four normal matched controls (one premenopausal and three postmenopausal) were evaluated. Samples were obtained every 30 min using a constant withdrawal pump. Growth hormone (GH) pulses were analysed by Cluster System. Twenty-four hour IC-GH was evaluated as area under the curve (AUC) and the following results were found: depressed (D) = 429.15 +/- 367.9 vs. controls (C) = 1281.07 +/- 379.77 (p < .008); nocturnal IC-GH: D = 220 +/- 274.0 vs. C = 739.52 +/- 378.15 (p < .02). No statistically significant differences were found between D and C in diurnal IC-GH or in the number of nocturnal or diurnal pulses. Adrenal (cortisol at 0800h, 2300h and post-suppression with 1 mg of dexamethasone) and thyroid (T3, T4, 0800h and 1700h TSH) evaluations did not show statistically significant differences between D and C women. In conclusion, patients with MDI present a decrease in total GH secretion at the expense of the nocturnal period, probably due to changes in the neurotransmitters that would be involved in depression.

Growth hormone deficiency (GHD) is an important clinical entity which has a significant impact on a child's development unless correctly diagnosed. The studies by our group which showed that in some growth retarded children, spontaneous GH secretion could be abnormal in the face of a normal response to GH provocative studies gave birth to the concept of growth hormone neurosecretory dysfunction (GHND).The neuroregulation of GH is extraordinarily complex involving the regulatory control of GH releasing hormone (GHRH) and somatostatin (SRIF) and several neurotransmitters. Recently, our group found that in Rhesus monkeys that had neurosurgically induced lesions of the arcuate and ventromedial nucleus (VMN) nuclei there was no significant alteration in the GH response to arginine, levodopa, and clonidine provocation after surgery but only a reduction in GH to insulininduced hypoglycemia and in spontaneous GH secretion.GHND is a form of GHD that needs to be correctly diagnosed since it is well known that GH plays an important role in other aspects of body function including growth, i. e. in carbohydrate, lipid, and protein metabolism, and a significant lack of GH may affect a child's well-being during its entire life unless appropriately treated.