PTSD-related hyperarousal assessed during sleep.

Posttraumatic stress disorder is widely understood to include "persistent symptoms of increased arousal." This presumption has rarely been tested under conditions in which effects of anticipatory anxiety could be ruled out. In this study, heart rate and electroencephalogram spectral power were assessed during sleep, a state free of most sources of artifact contaminating indices of tonic arousal. Fifty-six unmedicated nonapneic Vietnam combat-related inpatients with posttraumatic stress disorder (PTSD) and 14 controls spent 3 or more nights in the sleep laboratory during which their electrocardiograms and electroencephalograms were continuously recorded. Heart rate and electroencephalogram spectral power were quantified continuously off-line and averaged by sleep stage over all postadaptational nights. Sleep heart rate exhibited no group differences and no covariation with the severity of subjective hyperarousal reported by PTSD patients. PTSD patients exhibited a trend toward reduced low-frequency electroencephalogram spectral power during nonrapid-eye-movement (NREM) sleep. This reduction was significant during slow-wave sleep in those subjects producing scoreable slow-wave sleep. The relationship of rapid-eye-movement (REM) beta-band power to NREM beta-band power was different in PTSD patients and controls, with the patients exhibiting more beta in REM versus NREM sleep than controls. In patients, NREM sleep sigma-band electroencephalogram spectral power exhibited a positive correlation with subjective hyperarousal. Finally, a novel and surprisingly strong inverse correlation between REM-NREM sleep heart rate difference and REM percent of sleep was observed in PTSD patients only. In summary, peripheral and central measures of tonic arousal during sleep demonstrated contrastive relations to PTSD diagnostic and symptom status. The data suggest that more consideration should be directed to mechanisms of central arousal in PTSD.

Plasma norepinephrine kinetics in patients with posttraumatic stress disorder.

To determine whether basal sympathetic nervous system (SNS) function is increased in patients with posttraumatic stress disorder (PTSD), we used a radioisotope dilution technique to assess basal arterialized plasma norepinephrine (NE) kinetics in 12 men who were Viet Nam combat veterans with PTSD and six normal controls. In addition to determining the rates of appearance of NE into, and clearance of NE from, plasma, we measured basal arterialized plasma levels of epinephrine (EPI), and also vital signs, in both groups. Patients with PTSD actually manifested lower arterialized plasma levels of NE, and had lower rates of appearance of NE into plasma, than did controls. The rate of NE clearance from plasma was unaltered in PTSD patients. Patients with PTSD also showed a trend toward lower arterialized EPI levels than controls, but manifested a trend toward higher diastolic blood pressure. Our data indicate that basal SNS activity is not increased in patients with PTSD and that previous reports of increased resting SNS activity in this population may instead reflect SNS reactivity.

Sympathetic nervous system activity in major depression. Basal and desipramine-induced alterations in plasma norepinephrine kinetics.

BACKGROUND: To determine whether elevations of plasma norepinephrine (NE) in major depression represent increased sympathetic nervous system (SNS) activity and to assess the effects of desipramine hydrochloride on sympathetic function. METHODS: SNS activity was assessed in depressed patients and controls by an isotope-dilution, plasma NE kinetic technique using mathematical modeling and compartmental analysis. This approach provided estimates of the rate of NE appearance into an extravascular compartment, which is the site of endogenous NE release from SNS nerves, the corresponding rate of NE appearance into plasma, and the rate of NE clearance from plasma. RESULTS: Norepinephrine appearance into the extravascular and vascular compartments was significantly elevated in 17 depressed patients compared with that in 36 controls. The rate of NE clearance from plasma was similar in both groups. This is compatible with increased SNS activity in major depression. Desipramine, given for 2 days, significantly reduced the concentration of NE in plasma of patients and controls by markedly suppressing the rates of extravascular and vascular NE appearance, compatible with a short-term reduction in SNS activity. Desipramine prolonged the rate of NE clearance from plasma, consistent with a blockade of NE re-uptake into SNS nerve terminals. The initial suppression of SNS activity by desipramine was reversed by long-term (28 days) treatment of patients, with extravascular and vascular NE appearance rates returning to approximately basal levels. An associated rise in plasma NE concentrations compared with the baseline was attributable to a progressive reduction in plasma NE clearance. CONCLUSION: Sympathetic nervous system activity is elevated in major depression and is suppressed by short-term desipramine administration. The demonstration of SNS reactivation occurring with prolonged desipramine treatment is compatible with the theory that long-term treatment desensitizes CNS alpha 2-adrenergic receptors and emphasizes the value of examining the temporal course of responses to pharmacological challenges of neuroendocrine systems. Previously reported elevations of plasma NE during prolonged administration of tricyclic antidepressants are probably the result of a reduction in plasma NE clearance, not an increase in SNS activity.

Evidence for two differentially regulated populations of peripheral beta-endorphin-releasing cells in humans.

In the current study we tested the hypothesis that human plasma beta-endorphin (beta E) is derived from at least two subpopulations of beta E-releasing cells: one sensitive to glucocorticoids as well as to dopamine (DA; regulated analogously to the corticotrophs of the rat pituitary), and one insensitive to glucocorticoids but sensitive to DA (regulated analogously to the melanotrophs of the rat pituitary). To test this hypothesis, human plasma levels of ACTH, cortisol, and beta E-like immunoreactivity were measured at baseline and after haloperidol treatment (0.05 mg/kg, i.v.) in two experimental groups, one pretreated with dexamethasone (1.5 mg) and one pretreated with placebo. Plasma PRL levels were also measured in both groups as an indicator of DA receptor blockade. Dexamethasone partially suppressed both baseline and haloperidol-stimulated levels of human plasma beta E-like immunoreactivity, whereas it completely suppressed both basal and haloperidol-stimulated levels of ACTH and cortisol and had no statistically significant effect on either basal or haloperidol-stimulated PRL levels. These data support a negative feedback effect of glucocorticoids on one DA-sensitive cell population that releases both ACTH and beta E (corticotroph like), but not on a second cell population that releases beta E but not ACTH.

Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor in human subjects.

To assess the effect of desipramine (DMI) on corticotropin-releasing-factor (CRF) activity in the central nervous system, we measured cerebrospinal fluid (CSF) concentrations of CRF in healthy volunteers following short-term administration of DMI or placebo. DMI administration for 2 days was associated with a significant dose-related reduction in CRF concentrations. There was a nonsignificant 6% reduction in CRF concentrations among the 10 subjects who received 50 mg DMI (delta CRF: -3 +/- 2 pg/ml) and a significant 14% fall in the CRF concentrations of the eight subjects who received 100 mg DMI (delta CRF: -8 +/- 3 pg/ml). The mean CSF concentration of CRF was unchanged in the six subjects randomized to placebo (delta CRF: 1 +/- 5 pg/ml). DMI administration had no effect on CSF norepinephrine concentrations (n = 24) or on plasma cortisol (n = 25). We conclude that short-term administration of DMI in healthy volunteers is associated with a dose-related reduction in CSF concentrations of CRF.

Basal sympathoadrenal function in posttraumatic distress disorder.

Research has consistently shown that patients with posttraumatic stress disorder (PTSD) manifest greater changes in heart rate, blood pressure, and plasma epinephrine than controls when exposed to trauma-related laboratory stressors. However, findings are equivocal as to whether PTSD subjects differ from controls on basal, or tonic, measures of autonomic activity. In this study, PTSD patients (n = 11) and asymptomatic controls (n = 11) were compared on measures of basal sympathoadrenal function, including plasma norepinephrine and epinephrine as well as heart rate and blood pressure. Results showed that PTSD patients were not significantly different from control subjects on any measure. Although phasic alterations in autonomic function in PTSD have been consistently found in previous research, this study suggests that tonic sympathetic nervous system activity in PTSD patients may not differ from that of healthy controls.

Effects of yohimbine on human sympathetic nervous system function.

The alpha 2-adrenergic receptor antagonist yohimbine is often used as a neuroendocrine probe in human studies, in which it is assumed to increase plasma norepinephrine (NE) by increasing sympathetic outflow. In this study we have tested that assumption by using a radioisotope dilution technique to measure norepinephrine (NE) kinetics in arterialized plasma after administration of oral yohimbine (20 or 40 mg) or placebo to normal young men. In agreement with previous studies, we found that yohimbine causes dose-dependent increases in blood pressure, heart rate, and plasma NE. We further found that the increase in plasma NE is, in fact, due to an increase in the rate of appearance of NE into plasma and not to reduced NE clearance from plasma. In addition, we found that yohimbine causes a dose-dependent increase in plasma epinephrine, which had not been found in studies measuring catecholamines in venous plasma. We conclude that yohimbine increases plasma NE levels by increasing the rate of NE release from sympathetic nerves, and probably increases epinephrine release from the adrenals.

Autonomic responses to stress in Vietnam combat veterans with posttraumatic stress disorder.

This study tested the hypothesis that combat veterans with posttraumatic stress disorder (PTSD) experience sympathetic nervous system activation in response to war-related laboratory stimuli. Circulating plasma catecholamines, vital signs, and affect ratings were measured in 10 Vietnam combat veterans with PTSD and 11 control subjects, during and after viewing combat and noncombat stress films. PTSD subjects responded more strongly than controls to the combat film, with greater increases in plasma epinephrine, pulse, blood pressure, and subjective distress. The increases in autonomic activity of PTSD subjects was more pronounced and long lasting in response to the combat film than to the noncombat film, but type of film had no systematic effect on control subjects' responses. These findings are consistent with biological models that posit sympathoadrenal activation in response to memory-evoking cues of traumatic events in PTSD.

Localization and measurement of neurotransmitter receptors in rat and human brain by quantitative autoradiography.

Receptors for neurotransmitters can be visualized and characterized using in vitro tissue slice binding techniques and quantitative autoradiography. In this article, the general methods used in studies of this type are outlined and specific application to the study of catecholamine and neuropeptide receptors in rat and human brain tissue are described. Receptor autoradiography is used to examine regulation of dopamine receptor density in response to denervation and replacement of dopamine using brain transplants. Morphological and pharmacological aspects of vasopressin receptor ontogeny in the rat brain are examined. Finally, autoradiographic data on catecholamine receptor localization and characterization in the human hypothalamus, locus coeruleus, and frontal cortex are presented and discussed with reference to their applications in the study of neuropsychiatric disorders such as schizophrenia and senile dementia of the Alzheimer's type.

Age and alpha-2 adrenergic regulation of plasma norepinephrine kinetics in humans.

To investigate whether the age-related elevation of plasma norepinephrine (NE) is due to impaired alpha-2 adrenergic inhibition of sympathetic nervous system (SNS) outflow, arterialized plasma NE kinetics were measured before and 120 to 140 min after 1.5 and 5.0 micrograms m/kg oral clonidine in 6 old (57 to 78 years) and 8 young (25 to 39 years) normotensive male volunteers. Baseline plasma NE levels were higher in old compared with young men (M +/- SEM, 355 +/- 58 vs. 197 +/- 22 pg/ml, p less than .02). Clonidine produced significant (p less than .05) dose-related reductions in plasma NE, NE appearance rate, NE clearance, and mean arterial blood pressure (MAP) in both groups. There was no difference between old and young men in response to low dose clonidine. Following the higher dose, both groups had similar suppression of plasma NE (-51 +/- 7% vs. -58 +/- 2%, p greater than .05) and NE appearance (-60 +/- 6% vs. -62 +/- 2%, p greater than .05), but older men had a greater fall in NE clearance (-20 +/- 2% vs. -10 +/- 1%, p less than .003) and MAP (-28 +/- 3% vs. -10 +/- 4%, p less than .006). These findings suggest that sensitivity to alpha-2 receptor-mediated suppression of plasma NE and NE appearance is not diminished in elderly men.

Antipsychotic drugs and plasma vasopressin in normals and acute schizophrenic patients.

Elevated plasma vasopressin concentrations have been documented in antipsychotic drug-treated patients as well as a drug-free acutely psychotic patients. To evaluate the effects of antipsychotic drugs on plasma vasopressin, we measured vasopressin response to a single dose of intramuscular chlorpromazine or intravenous haloperidol in normal individuals and to 2 weeks of oral antipsychotics in patients with acute schizophrenia. Neither intramuscular chlorpromazine nor intravenous haloperidol affected plasma vasopressin in normals, except in one subject who developed high plasma vasopressin concentrations coincident with marked hypotension following chlorpromazine. Prior to antipsychotics, two acute schizophrenia patients had elevated plasma vasopressin concentrations, which normalized during antipsychotic drug treatment. We conclude that antipsychotics do not directly stimulate vasopressin release, but may indirectly stimulate vasopressin release by well-described baroreceptor reflex mechanisms if hypotension occurs. Also, acute schizophrenia may be associated with increased plasma vasopressin levels in some patients.

Haloperidol increases plasma beta endorphin-like immunoreactivity and cortisol in normal human males.

To investigate possible central dopaminergic regulation of beta-endorphin-like immunoreactivity (beta E-LI) and adrenocorticotropin (ACTH) release in humans, we gave the dopamine antagonist haloperidol or placebo intravenously to twelve normal male subjects and measured beta E-LI and cortisol for 120 minutes following injection. Haloperidol, but not placebo, produced significant increases in plasma beta E-LI and cortisol. These findings suggest that central dopaminergic pathways such as the tuberohypophyseal system may participate in regulation of the secretion of beta E and ACTH from the human pituitary.