Neuroendocrine and psychophysiologic responses in PTSD: a symptom provocation study.
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Biological research on post-traumatic stress disorder (PTSD) has focused on autonomic, sympatho-adrenal, and hypothalamo-pituitary-adrenal (HPA) axis systems. Interactions among these response modalities have not been well studied and may be illuminating. We examined subjective, autonomic, adrenergic, and HPA axis responses in a trauma-cue paradigm and explored the hypothesis that the ability of linked stress-response systems to mount integrated responses to environmental threat would produce strong correlations across systems. Seventeen veterans with PTSD, 11 veteran controls without PTSD, and 14 nonveteran controls were exposed to white noise and combat sounds on separate days. Subjective distress, heart rate, skin conductance, plasma catecholamines, ACTH, and cortisol, at baseline and in response to the auditory stimuli, were analyzed for group differences and for patterns of interrelationships. PTSD patients exhibited higher skin conductance, heart rate, plasma cortisol, and catecholamines at baseline, and exaggerated responses to combat sounds in skin conductance, heart rate, plasma epinephrine, and norepinephrine, but not ACTH. The control groups did not differ on any measure. In canonical correlation analyses, no significant correlations were found between response systems. Thus, PTSD patients showed heightened responsivity to trauma-related cues in some, but not all, response modalities. The data did not support the integrated, multisystem stress response in PTSD that had been hypothesized. Individual response differences or differing pathophysiological processes may determine which neurobiological system is affected in any given patient. (+info)
Negative chronotropic effects of fentanyl attenuate beneficial effects of dobutamine on oxygen metabolism: hemodynamic and pharmacokinetic interactions.
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Opioids are well known to cause cardiovascular depression. The aim of the present investigation was to determine whether an interaction of opioid derivatives with catecholamines might be involved in these hemodynamic alterations. Six comatose patients were enrolled into a prospective, nonrandomized pilot trial. All patients first received a continuous i.v. infusion of dobutamine (10 microgram. kg-1. min-1) paralleled by continuous administration of midazolam (0.4 mg. kg-1. h-1); thereafter, fentanyl was added i.v. (4 microgram. kg-1. h-1). Hemodynamic parameters as well as dobutamine and endogenous catecholamines plasma levels were determined. The mean arterial blood pressure did not change significantly during the whole study period. The continuous administration of dobutamine (steady-state plasma concentrations: 217 +/- 118 ng. ml-1) increased the beta1-adrenergic receptor-mediated hemodynamic parameters such as heart rate, stroke volume index, cardiac index, and oxygen delivery index (p <.05). The concomitant administration of fentanyl decreased the heart rate-dependent hemodynamic parameters (p <.05), suggesting that fentanyl antagonizes the chronotropic effects of dobutamine. In parallel, dobutamine plasma levels increased significantly (275 +/- 165 ng. ml-1; p <.05). Noteworthy, after administration of fentanyl, oxygen delivery and consumption index returned to baseline values. Radioligand binding experiments on rat cardiac ventricular microsomes ruled out a direct interaction of fentanyl with beta-adrenergic receptors and, more importantly, a fentanyl-induced inhibition of beta-adrenergic receptor G protein coupling. Our observations suggest that fentanyl inhibits the frequency-related hemodynamic changes induced by dobutamine. The underlying mechanism is independent of beta-adrenergic receptors, but is powerful enough to abolish the salutary effect of dobutamine on oxygen delivery and consumption. (+info)
Effect of chronic social stress on delta-opioid receptor function in the rat.
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Previous studies have shown that stressors modify endogenous opioid systems. However, the consequences of social stress on the function of endogenous opioid systems is not well documented. The present studies investigated the effect of rank and housing condition on response to SNC-80, a delta receptor agonist. Triad-housed rats were assessed for dominance status by their behavior and alteration in body weights. At 3 and 50 days, triad- and individually housed rats were injected with SNC-80 (35 mg/kg i.p.) or saline, and evaluated using a test battery consisting of open field behaviors, rectal temperature, analgesia, and air-puff-induced ultrasonic vocalizations. After 50 days of housing, plasma corticosterone, adrenal catecholamines, and the density of cyclic[D-penicillamine2-D-penicillamine2]enkephalin-stimu lat ed guanylyl 5'-[gamma[35S]thio]-triphosphate binding in the prefrontal cortex, the amygdala, nucleus accumbens, thalamus, arcuate, and median eminence were also determined. The first 24 h of triad housing resulted in loss of body weight in subdominant (betas and gammas) but not dominant alpha rats. SCN-80-induced hypothermia was smaller, and there was no depression of headpoke and locomotor behavior in the periphery and the center of the field of alpha rats, in contrast to subdominant and singly housed rats. Rank status did not influence SNC-80's analgesic effect or its inhibition of air-puff-induced ultrasonic vocalizations. Plasma corticosterone levels of alphas and gammas were lower compared with betas and singly housed rats. Agonist stimulation of delta receptor guanylyl 5'-[gamma[35S]thio]-triphosphate binding was lateralized in prefrontal cortex and amygdala, but not nucleus accumbens. Binding was highest in all brain areas of singly housed rats and lowest in the thalamus of beta and of gamma rats. Lateralized binding in amygdala, high locomotor activity, and sensory sensitivity correlated positively with greater sensitivity to SNC-80-induced depression in these measures. Higher binding in the right amygdala correlated with higher plasma corticosterone levels. These findings indicate that dominant rats displayed stimulant rather than depressant responses to delta-opioid activation. Therefore in rodents rank-related stress can alter responsiveness of the endogenous opioid system, and dominance can increase the excitatory effects of delta agonists. (+info)
Brefeldin A increases the quantal size and alters the kinetics of catecholamine release from rat adrenal chromaffin cells.
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The fungal metabolite, brefeldin A (BFA), is known to inhibit guanine nucleotide exchange on the ADP-ribosylating factors that are involved in vesicle membrane trafficking. Here, we investigated the action of BFA on Ca2+-regulated exocytosis in single rat adrenal chromaffin cells. Incubation of chromaffin cells with BFA (1 or 10 microM) for 2 h effectively disrupted the Golgi membranes but did not affect the pattern of catecholamine release triggered by high extracellular K+, which was monitored with carbon fiber amperometry along with cytosolic Ca2+ measurement. The BFA treatment, however, increased the mean quantal size of catecholamine-containing vesicles and the occurrence of amperometric events with a "foot" or "stand alone" signal (which reflects sluggish or incomplete dilation of the fusion pore). To examine whether BFA altered the Ca2+-dependence of exocytosis, we employed the whole-cell recording technique in conjunction with the capacitance measurement to measure exocytosis evoked from the entire cell during voltage-gated Ca2+ entry. Our results suggested that BFA treatment did not alter either the initial rate of capacitance increase or the total amount of capacitance increase. Therefore, in chromaffin cells, BFA treatment affects Ca2+-regulated exocytosis predominantly by increasing the quantal size and by slowing the fusion kinetics of some vesicles. (+info)
Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice.
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Deficiency of 21-hydroxylase (21-OH), one of the most common genetic defects in humans, causes low glucocorticoid and mineralocorticoid production by the adrenal cortex, but the effect of this disorder on the adrenomedullary system is unknown. Therefore, we analyzed the development, structure, and function of the adrenal medulla in 21-OH-deficient mice, an animal model resembling human congenital adrenal hyperplasia. Chromaffin cells of 21-OH-deficient mice exhibited ultrastructural features of neuronal transdifferentiation with reduced granules, increased rough endoplasmic reticulum and small neurite outgrowth. Migration of chromaffin cells in the adrenal to form a central medulla was impaired. Expression of phenylethanolamine-N-methyltransferase (PNMT) was reduced to 27 +/- 9% (P<0.05), as determined by quantitative TaqMan polymerase chain reaction, and there was a significant reduction of cells staining positive for PNMT in the adrenal medulla of the 21-OH-deficient mice. Adrenal contents of epinephrine were decreased to 30 +/- 2% (P<0. 01) whereas norepinephrine and dopamine levels were reduced to 57 +/- 4% (P<0.01) and 50 +/- 9% (P<0.05), respectively. 21-OH-deficient mice demonstrate severe adrenomedullary dysfunction, with alterations in chromaffin cell migration, development, structure, and catecholamine synthesis. This hitherto unrecognized mechanism may contribute to the frequent clinical, mental, and therapeutic problems encountered in humans with this genetic disease. (+info)
Physiological changes in Pachinko players; beta-endorphin, catecholamines, immune system substances and heart rate.
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Pachinko is a popular form of recreation in Japan. However, in recent years, along with Pachinko's popularity, "Pachinko dependence" has become topical news. The purpose of this study was to investigate beta-endorphin, catecholamines, immune system responses and heart rate during the playing of Pachinko. The following significant results were observed. (1) Plasma concentration of beta-endorphin increased before playing Pachinko and while in the Pachinko-center (p < 0.05). (2) Beta-endorphin and norepinephrine increased when the player began to win (i.e. at "Fever-start") compared to baseline (p < 0.05). (3) Beta-endorphin, norepinephrine and dopamine increased when the winning streak finished (i.e. at "Fever-end") compared to baseline (p < 0.05-0.01). (4) Norepinephrine increased past 30 minutes after "Fever-end" compared to baseline (p < 0.05). (5) Heart rate increased before "Fever-start" compared to baseline, peaked at "Fever-start" and rapidly decreased to match rates measured at rest. But the increase was observed from 200 seconds after "Fever-start" (p < 0.05-0.001). (6) There was a positive correlation between the number of hours subjects played Pachinko in a week and the differences between beta-endorphin levels at "Fever-start" and those at rest (p < 0.05). (7) The number of T-cells decreased while the number of NK cells increased at "Fever-start" compared to baseline (p < .05). These results suggest that intracerebral substances such as beta-endorphin and dopamine are involved in the habit-forming behavior associated with Pachinko. (+info)
Neuronal control of catecholamine secretion from chromaffin cells in the rainbow trout (Oncorhynchus mykiss).
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The goal of the present investigation was to assess the relative involvement of nicotinic and muscarinic cholinergic receptors in the neuronal control of catecholamine secretion from the chromaffin tissue of rainbow trout (Oncorhynchus mykiss). This was accomplished by first developing and validating a nerve-stimulating technique able specifically to activate the nerve fibres innervating the chromaffin cells in order to elicit secretion of catecholamines. Using an in situ saline-perfused posterior cardinal vein preparation, it was demonstrated that whole-body field stimulation caused specific voltage-dependent neuronal stimulation of adrenaline and noradrenaline secretion. The contribution of non-specific depolarization was negligible. Several experimental results confirmed the specificity of the field stimulation technique. First, pre-treatment with neostigmine (an anticholinesterase) prolonged and more than doubled the amount of adrenaline secreted in response to electrical stimulation. Second, pre-treatment with the nicotinic receptor antagonist hexamethonium inhibited the electrically evoked secretion of adrenaline and noradrenaline. Third, perfusion with Na+-free saline or removal of the spinal cord abolished secretion of both catecholamines in response to the electrical stimulus. By using the field stimulation technique, this study is the first to demonstrate conclusively a role for muscarinic receptors in catecholamine secretion from trout chromaffin cells. Specifically, muscarinic cholinergic stimulation enhances nicotinic-evoked secretion of catecholamines and, under intense stimulation, may directly cause secretion. The results of the present study suggest the presence of muscarinic receptors on rainbow trout chromaffin cells with a functional role in the cholinergic control of catecholamine secretion. (+info)
Potentiation of quantal catecholamine secretion by glibenclamide: evidence for a novel role of sulphonylurea receptors in regulating the Ca(2+) sensitivity of exocytosis.
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Electrochemical detection of quantal catecholamine release from PC-12 cells revealed that glibenclamide, an inhibitor of ATP-sensitive K(+) channels, potentiated Ca(2+)-dependent exocytosis evoked by raised extracellular [K(+)] and by exposure of cells to caffeine. Glibenclamide was without effect on voltage-gated Ca(2+) currents, membrane potential, or rises of [Ca(2+)](i) evoked by either raised extracellular [K(+)] or caffeine. The dependence of K(+)-evoked secretion on extracellular Ca(2+) was shifted leftward in the presence of glibenclamide, with a small increase in the plateau level of release, suggesting that glibenclamide primarily increased the Ca(2+) sensitivity of the exocytotic apparatus. Enhancement of secretion by glibenclamide was reversed by pinacidil and cromakalim, indicating that the effects of glibenclamide were mediated via an action on a sulfonylurea receptor. These results demonstrate that sulfonylurea receptors can modulate Ca(2+)-dependent exocytosis via a mechanism downstream of Ca(2+) influx or mobilization. (+info)