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M F Dallman

Publications and source records attributed to M F Dallman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Chronic cold in adrenalectomized, corticosterone (B)-treated rats: facilitated corticotropin responses to acute restraint emerge as B increases.

Small elevations in corticosterone (B) administered exogenously exert potent inhibitory effects on both basal and stress-induced ACTH secretion. However, under conditions of chronic stress with chronic elevations in B, the hypothalamo-pituitary-adrenal system appears to balance the negative feedback signal of B with central neural facilitation so that the system remains fully responsive to acute stressors. In these studies, we tested whether: 1) circulating B concentrations affect responses to acute restraint in rats exposed to 5 days at 5-7 C (cold), compared with room temperature (control); and 2) facilitated ACTH secretion can be explained by increased CRF or vasopressin messenger RNA (mRNA) levels in the hypothalamic parvocellular paraventricular nuclei (PVN). Rats were adrenalectomized and supplied with B in doses that fixed plasma B at constant levels between approximately 2 and 20 microg/dl; rats were placed in cold or remained as controls. Increasing concentrations of fixed B decreased basal ACTH similarly in both groups. By contrast, as B levels increased, ACTH responses to restraint also increased in cold vs. control rats. Semiquantitative analysis of CRF mRNA by in situ hybridization revealed decreases of similar magnitude in both groups with increasing fixed B. Vasopressin mRNA levels also decreased with increasing fixed B in both groups, but with slightly less sensitivity to inhibition by B in cold exposed rats. Taken together, the decreases in mRNA for these major ACTH neuropeptide secretogogues in the parvocellular PVN are unlikely to explain facilitated ACTH responses in chronically stressed rats. We conclude that a brain site is stimulated by B that is proximal to the PVN; feedforward, positive effects of B are thus implicated in mediation of prior stress-induced facilitation of acute hypothalamo-pituitary-adrenal responses to stress.

Adrenalectomy↗
PubMed1996

The hypothalamic ventromedial nuclei couple activity in the hypothalamo-pituitary-adrenal axis to the morning fed or fasted state.

Function in the adrenocortical system is markedly altered by availability of food. Basal activity is lowest and stress responsivity highest in the morning when nocturnal rats eat approximately 90% of their daily calories during the dark. After an overnight fast, basal corticotrophin and corticosteroid levels are elevated, and responsivity to stressors is decreased. Central neural sites that control these changes are unidentified. The hypothalamic ventromedial nuclei (VMN) appear to signal satiety; lesions result in increased food intake, obesity, and elevated basal insulin and corticosteroids. Thus, the VMN are good candidates for calorically mediated control of adrenocortical system function in satiated rats. We injected colchicine into the VMN to cause reversible inhibition of activity (Avrith and Mogenson, 1978) and tested the effects on basal and stimulated function in the adrenocortical system. Colchicine-injected rats that fed ad libitum exhibited increased basal but reduced corticotrophin and corticosterone responses to restraint in the morning compared with controls. By contrast, after an overnight fast, control rats had increased basal adrenocortical hormones and decreased stress responses that did not differ from colchicine-injected rats. Colchicine was visualized within cells in the VMN for up to 5 d using fluorescein/colchicine, and the treatment did not cause increased gliosis; moreover, the functional effects of the injections were reversed within 15 d. We conclude that (1) the VMN serve to couple activity in the adrenocortical system to energy intake and (2) discrete colchicine injections provide a behaviorally and neuroendocrinologically useful period of inhibition without causing permanent functional damage.

Animals↗
PubMed1996

Predominately glucocorticoid agonist actions of RU-486 in young specific-pathogen-free Zucker rats.

Previous studies have demonstrated antiglucocorticoid actions for the progesterone receptor antagonist RU-486. In one study, daily administration of this drug for 2 wk decreased food intake (FI) and body weight gain (delta BW) in obese, but not lean, conventionally housed 5-wk-old female Zucker rats. We recently found that 2-wk administration of RU-486 attenuated delta BW in lean but not obese 12-wk-old male Zucker rats without affecting FI. To examine the actions of RU-486 and its effects on FI and delta BW in young (5 wk old) specific-pathogen-free (SPF) male and female Zucker rats, RU-486 was administered at 30 mg.kg-1.day-1 subcutaneously for 14 days. RU-486 did not affect FI in obese or lean male or female rats. RU-486 increased adrenal weight (P < 0.05) overall and in lean female rats and modestly decreased inguinal fat weight overall and in obese female rats (P < 0.01), suggesting some antiglucocorticoid activity in these animals. However, RU-486 also decreased thymus weight by 18-31% (P < 0.0001), increased plasma glucose by 10-16 mg/dl (P < 0.002), and increased plasma insulin by 47% in obese male rats (P < 0.028), demonstrating glucocorticoid agonist actions for the drug. Plasma corticosterone (B) and adrenocorticotropic hormone (ACTH) were elevated in vehicle-treated obese female and male rats by 150-360% (P < 0.0025) and 32-38% (P < 0.05), respectively, compared with lean rats. RU-486 treatment lowered the elevated plasma B and ACTH levels in obese female and male rats (both P < 0.02 vs. vehicle), a glucocorticoid agonist effect. We conclude that in young SPF Zucker rats 1) RU-486 administration does not alter FI or delta BW, 2) RU-486 has predominately glucocorticoid agonist actions in several tissues, 3) obese animals have increased hypothalamic-pituitary-adrenal (HPA) axis activity (plasma B and ACTH), and 4) RU-486 administration suppresses the HPA axis in obese rats.

Adipose Tissue↗
PubMed1996

Behavioral, endocrine, and hypothalamic responses to involuntary overfeeding.

The suppression of food intake after a period of forced overfeeding is potent and long lasting, yet little is known of the underlying mechanisms for this regulatory response. Rats were overfed via a surgically implanted gastrostomy tube. During overfeeding, plasma insulin and corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus were elevated compared with controls and with overfed rats allowed 3 days to recover from the overfeeding regimen such that body weight returned to the level of controls. In contrast, rats that were not overfed but were pair-fed to the low spontaneous food intake of previously overfed rats lost weight and had significantly reduced plasma insulin and elevated mRNA for neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus. The results indicate that overfeeding produces an activation of hypothalamic CRH system that may contribute to the hypophagia that accompanies involuntary overfeeding. Furthermore, the hypothalamic NPY response to food restriction is not tied to low food intake per se, but rather to negative energy balance.

Animals↗
PubMed1996

Hyperinsulinemia in rats with obesity-inducing amygdaloid lesions.

Electrolytic lesions of the posterodorsal aspects of the medial division of the extended amygdala in female rats result in hyperphagia and excessive weight gain. In the present study, the effects of such lesions on plasma insulin, glucose, corticosterone, and adrenocorticotropic hormone were assessed during a period of food restriction and again after a 15-day period of food ad libitum. Compared with control animals, the rats with amygdaloid lesions were hyperinsulinemic under both conditions and gained substantially more weight when fed ad libitum. No difference between groups was observed for the other hormones. It is concluded that damage to the posterodorsal aspects of the medial amygdala results in a primary metabolic dysfunction that accounts, at least in part, for the overeating and excessive weight gain.

Amygdala↗
PubMed1995

The neural network that regulates energy balance is responsive to glucocorticoids and insulin and also regulates HPA axis responsivity at a site proximal to CRF neurons.

The structure of a large neural system that responds to and regulates energy balance and that encompasses that PVN and activity of the HPA axis has begun to emerge from these experiments (Fig. 6). Several large loops have been delineated within this context of the maintenance of energy balance. Corticosteroids stimulate both feeding and insulin secretion. The actions of corticosteroids in the periphery are catabolic, causing mobilization of energy stores; their actions in the central nervous system are stimulatory to energy acquisition (food intake). By contrast, the action of insulin in the periphery is anabolic, causing energy storage; its action in the central nervous system is inhibitory to energy acquisition (food intake). At the level of the CNS, insulin inhibits and corticosteroids stimulate expression of NPY mRNA in the arcuate nuclei, and these actions may explain, in part, the reciprocal actions of the hormones on energy acquisition. Thus over the long term, stimulation of insulin secretion by corticosteroids tends to supply an automatic brake on the effects of corticosteroids on feeding. The neural system that controls energy balance and responds to the reciprocal signals of corticosterone and insulin also regulates responsivity to restraint stress in the HPA axis. The low-amplitude ACTH responses to restraint, corticosteroid feedback, and prior stress-induced facilitation that are observed under conditions of relative fasting in the PM can be produced in the AM by a 14-h, overnight fast. By contrast, NPY injected ivt stimulates identical ACTH responses in the AM in fed rats and in rats fasted overnight, suggesting that NPY acts to stimulate CRF secretion at a site closer to the PVN than the stress of restraint, which is filtered through the neural energy balance system. In the periphery, corticosteroids and insulin also have reciprocal effects on energy storage; effects that are opposite those exerted in the CNS on energy acquisition. Thus, together, the two hormones may be construed as a bihormonal system that regulates overall energy balance. Although under normal conditions this system is well designed to accomplish energy balance, and provides a mechanism by which total energy stores may be increased appropriately (e.g., prior to hibernation or migration), it seems probable that under conditions of chronic stress, this regulatory system may be maladaptive. Chronic stress and glucocorticoid treatment cause increases in mean daily concentrations of both corticosteroids and insulin. Increases in the absolute levels of both hormones, with the normal ratio between them maintained, results in remodeling of body energy stores-away from muscle stores and toward fat stores, particularly abdominal fat stores. It seems quite likely that some conditions of abdominal obesity in man may be explained, at least in part, by increased activity in the HPA axis. Because abdominal obesity is associated with cardiovascular diseases, these responses, when they persist, are clearly maladaptive. Exploration of the role and control of the HPA axis in and by the larger neural network that regulates energy balance has to date been instructive. Clearly this work has just begun and is primarily still at the level of phenomenology. However, once the phenomenology is understood, mechanistic work can be performed that will flesh out our understanding of this very large and physiologically essential system.

Adrenal Cortex Hormones↗
PubMed1995

Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.

Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.

Amino Acid Sequence↗
PubMed1995

Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis.

Neuropeptide Y (NPY) is a powerful stimulus to food intake in the rat. Exogenous NPY given into the third ventricle or into the paraventricular nucleus (PVN) of the hypothalamus stimulates both food consumption as well as the hypothalamus-pituitary-adrenal (HPA) axis. Presumably NPY activates the adrenocortical system through direct stimulation of CRF containing cells in the PVN. Food intake is also a major regulator of adrenocortical activation. Rhythms in HPA axis activity follow rhythms in food consumption, and rats that have been food deprived overnight have inhibited HPA axis responses to restraint stress and corticosteroid feedback the following morning. To investigate the interaction of NPY with both feeding and HPA axis activation three sets of experiments were performed: Animals fed ad lib were injected icv with NPY (2.5 micrograms) and allowed access to food or not post injection; animals were fasted overnight prior to NPY injection; finally, dose response experiments were performed to examine the relative sensitivities of feeding and HPA axis activation to exogenous NPY. Ad lib fed animals allowed access to food after NPY injection had slightly greater ACTH responses to NPY while glucocorticoid and insulin responses were not significantly different from ad lib fed animals not allowed access to food post injection. Animals allowed to eat post injection had significantly decreased food consumption the night following injection, however, total 24 h food consumption was not different between these animals and those given food 8 h post NPY injection. In overnight fasted animals NPY injections produced ACTH responses of equal magnitude to those in ad lib fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Glucocorticoids and insulin: reciprocal signals for energy balance.

Signals that regulate long-term energy balance have been difficult to identify. Increasingly strong evidence indicates that insulin, acting on the central nervous system in part through its effect on neuropeptide Y (NPY), inhibits food intake. We hypothesized that corticosteroids and insulin might serve as interacting, reciprocal signals for energy balance, acting on energy acquisition, in part through their effects on hypothalamic NPY, as well as on energy stores. Because glucocorticoids also stimulate insulin secretion, their role is normally obscured. Glucocorticoids and insulin were clamped in adrenalectomized rats with steroid replacement and streptozotocin-induced diabetes. Glucocorticoids stimulated and insulin inhibited NPY mRNA and food intake. Glucocorticoids inhibited and insulin increased energy gain as determined by the change in body weight. When adrenalectomized diabetic rats were treated, corticosterone stimulated and insulin inhibited food intake, and, respectively, inhibited and increased overall energy gain. More than 50% of the variance was explained by regression analysis of the two hormones on food intake and body weight. Thus glucocorticoids and insulin are major, antagonistic, long-term regulators of energy balance. The effects of corticosterone and insulin on food intake may be mediated, in part, through regulation of hypothalamic NPY synthesis and secretion.

Adrenalectomy↗
PubMed1995

Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue.

Brown adipose tissue (BAT) contains glucocorticoid receptors; glucocorticoids are required for maintaining differentiated BAT in culture. These studies were performed to determine the effects of corticosterone on BAT thermogenic function and lipid storage. Rats were adrenalectomized and given subcutaneous corticosterone pellets in concentrations that maintained plasma corticosterone constant across the range of 0-20 micrograms/dl or were sham adrenalectomized. All variables were examined 5 days after surgery and corticosterone replacement. Measures of BAT function-thermogenic capacity [guanosine 5'-diphosphate (GDP) binding and uncoupling protein (UCP; a BAT-specific thermogenic protein)] and storage (BAT wet wt, protein, and DNA levels) were made. Plasma hormones (corticosterone, adrenocorticotropic hormone, insulin, 3,3',5-triiodothyronine, and thyroxine were measured. Corticosterone significantly affected BAT thermogenic measures: UCP content and binding of GDP to BAT mitochondria decreased with increasing corticosterone; GDP binding characteristics in BAT from similarly prepared rats examined by Scatchard analysis showed that maximum binding (Bmax) and dissociation constant (Kd) decreased with increasing corticosterone dose. BAT DNA was increased by adrenalectomy and maintained at intact levels with all doses of corticosterone; BAT lipid storage increased dramatically at corticosterone values higher than the daily mean level in intact rats. Histologically, the number and size of lipid droplets within BAT adipocytes increased markedly with increased corticosterone. White adipose depots were more sensitive to circulating corticosterone concentrations than were BAT depots and increased in weight at levels of corticosterone that were at or below the daily mean level of intact rats. We conclude that, within its diurnal range of concentration corticosterone acts to inhibit nonshivering thermogenesis and increase lipid storage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipocytes↗
PubMed1995

Glucocorticoids and insulin: complex interaction on brown adipose tissue.

Glucocorticoids and insulin effect long-term reciprocal changes in food intake and body weight. We tested the interactions of corticosterone and insulin on caloric efficiency, white adipose tissue (WAT) stores, and brown adipose tissue (BAT). Two experiments were performed: 1) adrenalectomized rats were treated with corticosterone with or without streptozotocin-induced diabetes and 2) adrenalectomized, corticosterone-treated, diabetic rats were treated with insulin. By 4-5 days later, > or = 50% of the variance in caloric efficiency, plasma triglycerides, and WAT stores was explained by regression of these variables on corticosterone (catabolic) and insulin (anabolic). When the ratio of the hormones was normal, but concentrations high, overall gain of energy stores decreased and energy was redistributed to fat. Both hormones were anabolic on BAT lipid storage; the hormones played a complex role in the regulation of uncoupling protein (UCP) in BAT. Although corticosterone inhibited and insulin stimulated UCP, these effects were only evident in diabetics and with normoglycemia, respectively. For BAT variables, < or = 50% of the variance was explained by regression on corticosterone and insulin, suggesting that the effects of these hormones are mediated through an intermediate such as sympathetic nervous system input to BAT.

Adipose Tissue↗
PubMed1995

Hypothalamic response to starvation: implications for the study of wasting disorders.

Weight loss is a potent stimulus to food intake in normal individuals. The persistence of anorexia in wasting disorders, therefore, implies a failure of this adaptive feeding response. We describe a model for the normal hypothalamic response to starvation composed of the stimulation of neuronal pathways that promote energy intake and storage coupled with the inhibition of pathways that exert opposing effects. This model provides a framework for investigating disturbances of the normal hypothalamic response to weight loss and suggests a specific mechanism by which cytokines contribute to wasting in acquired immune deficiency syndrome and other cachexic disorders.

Animals↗
PubMed1995

Ventromedial hypothalamic lesions inhibit corticosteroid feedback regulation of basal ACTH during the trough of the circadian rhythm.

We have determined the effects of bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) on activity in the hypothalamo-pituitary-adrenal (HPA) system. Acutely, during the first 5 days, lesions of the anterior-medial VMH caused loss of the diurnal rhythms in food intake and plasma corticosterone (B) levels. Plasma B concentrations were elevated during the time of the normal trough of the basal diurnal rhythm in HPA axis activity and the diurnal rhythm in food intake was abolished, in agreement with the results of others. Consistent with hyperactivity in the HPA axis, lesioned rats had increased adrenal weight, decreased thymus and body weights and decreased plasma transcortin concentrations. To determine how lesions of the VMH provoke these increases in activity of the HPA system, the sensitivity of ACTH in adrenalectomized, lesioned rats to replacement with exogenous B was determined under basal conditions during the trough (morning-AM) and peak (evening-PM) of the diurnal rhythm in HPA axis activity. ACTH in lesioned rats in the AM was insensitive to feedback over the very low range of plasma B of 1-4 micrograms/dl, whereas sham-lesioned controls exhibited the normal, high sensitivity of ACTH to B at this time of day. There was no difference between the sensitivity of ACTH to this low range of B in the PM in VMH- and sham-lesioned rats. Two to 5 weeks after VMH lesions, as found by others, mean daily plasma B levels did not differ from sham-lesioned controls; however, plasma B during the AM was still mildly elevated in these rats. Inhibition of plasma B in the PM by dexamethasone was less effective in lesioned rats. Although HPA system responses to hypoglycemia, corticotropin-releasing factor and ACTH were normal, the lesioned rats exhibited obesity, hyperinsulinemia, hyperglycemia, hypertension and tachycardia, all signs consistent with mild hyperactivity of the PHA axis. Occupancy of type I, high-affinity corticosteroid receptors is known to control basal activity of the HPA system during the trough of the diurnal rhythm and to interact with glucocorticoid receptors to affect basal activity during the peak of the diurnal rhythm and during AM stress. We conclude that VMH lesions disrupt transmission of inhibitory signals, mediated by occupancy of type I corticosteroid receptors, that are initiated by a B feed-back site.

Adrenal Cortex Hormones↗
PubMed1995

Aldosterone and dexamethasone both stimulate energy acquisition whereas only the glucocorticoid alters energy storage.

Corticosteroids stimulate and insulin inhibits energy acquisition (food intake); conversely, corticosteroids inhibit and insulin stimulates energy storage (body weight gain). Thus, together these hormones mediate long-term energy balance. This study tested whether the stimulatory action of corticosteroids on food intake was mediated by association with high affinity mineralocorticoid receptors (MRs) or lower affinity glucocorticoid receptors (GRs). Young male rats were adrenalectomized (ADX) and given vehicle (control) or streptozotocin (diabetic); subgroups of rats were infused with vehicle, aldosterone (Aldo, an MR agonist in vivo), dexamethasone (Dex, a GR agonist in vivo), or Aldo&Dex for the 5 days after ADX. Sham-ADX rats were included. Food intake, body weight gain, and epididymal white adipose and interscapular brown adipose tissue stores were weighed. ADX decreased food intake by approximately 24%, and food intake was not increased by diabetes as it was in sham-ADX rats. In control ADX rats, Dex, but not Aldo, stimulated insulin, and food intake was not significantly affected by either hormone; together, Aldo and Dex restored insulin and food intake to sham-ADX rats. Food intake in diabetic ADX rats was significantly increased by each treatment (ADX < Aldo < Dex < Aldo&Dex = sham). Aldo increased body weight through an increase in fluid volume (estimated by decreased plasma protein concentration); however, fat stores were not different from ADX. Dex reduced body weight in control rats but maintained fat stores; in diabetic rats, body weight and fat stores were less than or similar to ADX. We conclude that: 1) corticosteroids, acting through association with both MRs and GRs, stimulate food intake; 2) insulin counteracts the GR-mediated stimulation of food intake in control rats; and 3) Dex and insulin, which is stimulated by Dex, selectively maintain or increase body fat stores, probably at the expense of protein stores.

Adipose Tissue↗
PubMed1995

Corticosterone regulation of insulin-like growth factor I, IGF-binding proteins, and growth in streptozotocin-induced diabetic rats.

The experiments reported herein were conducted to determine how corticosterone regulates growth and plasma insulin-like growth factor (IGF) I and IGF-binding protein (IGFBP) concentrations in normal and streptozotocin (STZ)-induced diabetic rats. Males were bilaterally adrenalectomized (Ax) or sham Ax and given intravenous injections of 0, 30, or 65 mg STZ per kg body wt (0, 30, or 65 STZ) to induce varying degrees of insulin deficiency and implanted with 100-mg pellets containing 0, 40, or 80% corticosterone in cholesterol. Changes in plasma IGFBP concentrations were determined by Western ligand blotting or immunoblots. Neither IGFBP-5 nor IG-FBP-6 was detected in any of the treatment groups. Plasma IGFBP-2 was elevated and IGF-I was reduced in the nondiabetic Ax rats compared with sham Ax controls, but plasma IGFBP-3 and -4 were not significantly changed. Adrenalectomy had no affect on tibial growth or plasma IGFBP-1 in these animals. Plasma IGF-I, IGFBP-1 and -3, and tibial growth were equal among 0, 30, and 65 STZ Ax rats that did not receive corticosterone. Plasma IGFBP-4 was inversely related to the amount of STZ injected in these animals, and IGFBP-2 was elevated in those given the high dose of STZ. In the 0 STZ Ax rats, plasma IGF-I and IGFBP-3 increased in proportion to the corticosterone implant dose, but IGFBP-1 was unaffected. By contrast, IGF-I and IGFBP-3 were unaltered by corticosterone in the 30 STZ Ax rats, and IGFBP-1 increased in proportion with the dose of corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1994

Role of vagal afferents and spinal pathways modulating inhibition of bradykinin-induced plasma extravasation by intrathecal nicotine.

1. Nicotine, a major active component of tobacco smoke, has been shown to modulate the inflammatory response via both peripheral and central nervous system pathways. Recently we found that spinal intrathecal administration of nicotine dose-dependently inhibits bradykinin-induced plasma extravasation (BK-induced PE) in the knee joint of the rat and that the dose-response curve for the inhibition of BK-induced PE by intrathecal nicotine is shifted to the left, by six orders of magnitude, after surgical interventions in the abdominal cavity, which might have interrupted visceral afferents to the neuraxis. Therefore we focused, in this study, on the contribution of the vagal afferents to depression of BK-induced PE by intrathecal nicotine. Furthermore, the effect of acute spinalization at the level C6-C8 was investigated. The hypothesis was that impulse activity in vagal afferents has a pronounced inhibitory effect on the modulation of BK-induced PE by intrathecal nicotine and that spinal pathways are important in mediating this effect. 2. Chronic subdiaphragmatic vagotomy and elimination of vagal afferents, by neonatal capsaicin treatment or by application of kainic acid to the nodose ganglia, enhanced the potency of intrathecal nicotine depression of BK-induced PE, by six to seven orders of magnitude when compared with the control. 3. Acute subdiaphragmatic vagotomy enhanced the potency of intrathecal nicotine-induced depression of BK-induced PE (without changing its maximum effect), by about three to four orders of magnitude when compared with the sham-operated (control) animals (with intact vagus nerves).(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1994

Roles of type I and II corticosteroid receptors in regulation of basal activity in the hypothalamo-pituitary-adrenal axis during the diurnal trough and the peak: evidence for a nonadditive effect of combined receptor occupation.

Negative feedback regulation of basal activity in the hypothalamo-pituitary-adrenal (HPA) axis requires less corticosterone (B) at the trough (morning) than at the peak (evening) of the diurnal rhythm. It has been hypothesized that in the morning in rats, occupation of the high affinity, type I corticosteroid receptors is sufficient to inhibit adrenalectomy (ADX)-induced increases in plasma ACTH secretion, whereas in the evening, regulation occurs through the occupation of the lower affinity type II corticosteroid receptors. To examine this hypothesis, the sensitivity of ACTH to inhibition by two different doses of B or of dexamethasone (DEX) were compared in ADX rats killed in the morning or the evening (B has a higher affinity for type I receptors in vitro and in vivo; in vivo, DEX has a higher affinity for type II receptors). The requirement for greater concentrations of corticosteroids to inhibit ACTH secretion in the evening was verified. The effect of these treatments on the number of neurons immunoreactive for vasopressin (AVP) and on the expression of AVP messenger RNA (mRNA) in the parvocellular portion of the paraventricular nuclei was also examined. In the morning, plasma concentrations of B equivalent to the IC50 for the reduction of plasma ACTH in the morning reduced the amount of AVP mRNA, but not immunoreactive AVP cell number as compared with ADX rats. DEX reduced plasma ACTH in the morning but did not prevent high levels of expression of AVP mRNA or protein. AVP mRNA was more sensitive to B in the morning than in the evening. Antagonist to the type I receptor (spironolactone) given chronically to ADX rats treated with B increased plasma ACTH secretion at both times of day, even though the plasma B concentrations suggested occupancy of a large proportion of the type II receptors. To test the hypothesis that an interaction between the type I and II receptor is necessary for the control of HPA activity at the peak of the diurnal rhythm, ADX rats were given B or DEX, alone or in combination. DEX reduced evening plasma ACTH only in the presence of very low concentrations of B, suggesting that for full potency, type II receptor occupation requires type I receptor occupation. In summary, these results demonstrate that occupation of type I corticosteroid receptors is capable of controlling basal activity in the HPA axis in the morning and that in the evening, type I receptor occupation potentiates the inhibition of plasma ACTH by occupation of type II receptors.

Adrenocorticotropic Hormone↗