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Biomedical subjects

M A Kling

Publications and source records attributed to M A Kling.

At least 37 records · Page 2Linked to original sources
PubMed1994

Diurnal variation of cerebrospinal fluid immunoreactive corticotropin-releasing hormone levels in healthy volunteers.

CRH is not only secreted into hypophyseal protal blood where it is believed to regulate the circadian rhythm of pituitary-adrenal activity, but is also measurable in cerebrospinal fluid (CSF). Altered CSF immunoreactive CRH (IR-CRH) levels have been found in patients with a number of neuropsychiatric disorders and have been implicated in some of the symptoms of these disorders. To further study the potential functional relevance of CRH in human CSF, we examined whether a nonuniform temporal pattern of IR-CRH levels existed in CSF using hourly sampling over a 30-h period in six healthy volunteers. CSF was withdrawn continuously at 6 mL/h through a catheter placed in the lumbar subarachnoid space and connected to a miniroller pump and fraction collector. A significant diurnal variation in CSF IR-CRH levels was observed (P < 0.001), with highest levels between 1830-2330 h and lowest levels around 0730 h. This pattern was nearly opposite that of plasma cortisol levels, which showed the expected peak around 0800 h and nadir around 2000-2200 h. In addition, CSF IR-CRH levels in three of the six volunteers showed significant negative correlations with simultaneous plasma cortisol levels. These data suggest that CSF IR-CRH concentrations are negatively modulated by peripheral cortisol secretion, which may be one factor involved in the entrainment of this rhythm. Although the functional significance of this diurnal variation in CSF IR-CRH levels is unknown, the presence of a distinct temporal organization of CRH release into the CSF in humans is compatible with the idea that CSF may play a functional role in or otherwise reflect nonsynaptic information processing in the central nervous system. Diurnal factors should be taken into account in future studies of CRH concentrations in human CSF.

Adult↗
PubMed1994

Effects of electroconvulsive therapy on the CRH-ACTH-cortisol system in melancholic depression: preliminary findings.

Hypercortisolism is one of the most consistent biological abnormalities seen in patients with major depression, particularly the melancholic subtype. We present preliminary data regarding the effects of electroconvulsive therapy (ECT) on urinary-free cortisol (UFC) excretion and on the secretion of its principal regulatory hormone, corticotropin-releasing hormone (CRH), into the cerebrospinal fluid (CSF) of patients with major depression. Our preliminary results indicate that, while acute elevations in UFC may occur with the initiation of ECT or other antidepressant treatments, successful treatment with ECT is associated with a reduction in both UFC excretion and the diurnal pattern of CSF immunoreactive CRH levels. These findings are compatible with data in experimental animals that show reductions in hypothalamic CRH expression and pituitary-adrenal function with long-term antidepressant treatments.

Adrenocorticotropic Hormone↗
PubMed1994

Effects of local anesthetics on experiential, physiologic and endocrine measures in healthy humans and on rat hypothalamic corticotropin-releasing hormone release in vitro: clinical and psychobiologic implications.

Local anesthetics, given i.v. to treat cardiac arrhythmias and for regional anesthesia, exert prominent central nervous system side effects, such as sensory distortions and mood changes. In experimental animals, these drugs activate limbic structures, such as the amygdala, that may coordinately regulate sensory processing, mood and pituitary hormone secretion during stress. Clinically relevant i.v. doses of the short-acting local anesthetic procaine were administered to 17 healthy volunteers and topographic electroencephalographic (EEG) spectra, stress-responsive neuroendocrine and cardiovascular parameters and sensory-cognitive and mood changes were examined. Because corticotropin-releasing hormone (CRH) mimics the behavioral and physiologic responses to stress and activates limbic structures in experimental animals, the effects of procaine and lidocaine on immunoreactive CRH release from rat hypothalami in vitro were also explored. Procaine administration produced a dose-related increase in fast (21-50 Hz) EEG activity, a significant decrease in alpha EEG activity and dose-dependent increases in heart rate, systolic blood pressure and plasma adrenocorticotropic hormone, cortisol and prolactin secretion. Dose-dependent increases in sensory distortions involved virtually all modalities, particularly auditory, visual and somatosensory. Mood changes occurred in most subjects, including anxiety, euphoria and arousal. In vitro, procaine and lidocaine both produced significant dose-related increases in immunoreactive CRH release from rat hypothalami, maximal at 10(-6) M, that were blocked by carbamazepine, a limbic anticonvulsant used in the management of mood disorders. The electrophysiologic effects of procaine in these volunteers were analogous to local anesthetic effects in experimental animals and consistent with the activation of subcortical structures localized within the temporal lobe, such as the amygdala. The effects of procaine on stress-responsive neurohormones were similar to those of amygdala stimulation both in experimental animals and human subjects. The in vitro data suggested that procaine-induced pituitary-adrenal activation involves stimulation of hypothalamic CRH, although additional (e.g., limbic-hypothalamic) mechanisms may contribute in vivo. These data were compatible with a direct action of local anesthetics on limbic structures that might account for many of the central effects seen with the systemic use of these agents in clinical practice.

Adrenocorticotropic Hormone↗
PubMed1993

Facilitation of cocaine kindling by glucocorticoids in rats.

We report that glucocorticoids significantly facilitated the development of cocaine-induced kindled seizures. These results suggest that glucocorticoids may have effects on the development of kindled seizures which are similar to those of the neuropeptide, corticotropin-releasing hormone (CRH), with which they show a close functional relationship. These results may be of interest in the light of data showing that glucocorticoids increase CRH expression in the central nucleus of the amygdala, which is an important site for the development of kindling.

Animals↗
PubMed1993

Sex differences in sensitivity of the hypothalamic-pituitary-adrenal axis.

Two studies examined sex differences in responsiveness of the hypothalamic-pituitary-adrenal cortical axis, a major component of the stress response. The first measured pituitary-adrenal responses to ovine corticotropin-releasing hormone (oCRH) in 24 health men and 19 healthy women. Plasma adrenocorticotropin hormone (ACTH) response to oCRH were significantly greater among women than among men. In contrast, cortisol concentrations were similar in both groups, though elevations were more prolonged in women. Differences in corticotropin-releasing activity between men and women may help account for these findings; such differences in central components of the stress response might play a role in the known epidemiological differences in diseases of stress system dysregulation between men and women.

Adrenocorticotropic Hormone↗
PubMed1993

Quantitative electroencephalographic correlates of steroid administration in man.

Elevated levels of circulating corticosteroids are frequently associated with behavioral alterations in man, although the mechanisms by which corticosteroids may affect behavior are poorly understood. To evaluate possible effects of exogenous corticosteroids on brain electrophysiological functioning and the relationship of such effects to behavioral and biochemical changes, we administered prednisone (80 mg p.o. daily for 5 days) in a double-blind manner to 11 medically healthy volunteers. Quantitative electroencephalogram analysis was performed following 4 days of prednisone administration and during the preceding and ensuing placebo administration periods. Central theta wave brain electrical activity significantly increased following prednisone administration and returned to baseline following prednisone withdrawal. This effect was directly correlated with prednisone-induced increases in subjective sadness ratings and with decreases in self-rated energy and well-being. Prednisone-induced reductions in peak alpha wave activity were also directly correlated with increases in subjective sadness and Symptom Checklist-90 ratings and with decreases in self-rated 'hypomanic' symptoms. Further, prednisone-induced increases in theta activity were significantly correlated with prednisone-induced decreases in CSF levels of somatostatin-like immunoreactivity, and prednisone-induced decreases in peak alpha activity were significantly correlated with decreases in CSF levels of norepinephrine and with relative increases (or lesser decreases) in CSF levels of beta-endorphin and beta-lipotropic hormone. This preliminary report of the concomitant development of prednisone-induced changes in brain electrical activity, neurochemistry and behavior highlights areas for future exploration in the study of corticosteroid effects on behavior in man.

Adult↗
PubMed1993

Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing's disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion.

To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushing's disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushing's disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 +/- 2.9 vs. 37.4 +/- 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 +/- 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushing's disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r2 = 0.90; d.f. = 22; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-Releasing Hormone↗
PubMed1993

Effects of the glucocorticoid antagonist RU 486 on pituitary-adrenal function in patients with anorexia nervosa and healthy volunteers: enhancement of plasma ACTH and cortisol secretion in underweight patients.

To further explore whether the hypercortisolism of anorexia nervosa reflects an alteration in the set point for corticotropin-releasing hormone (CRH) secretion or is a manifestation of glucocorticoid resistance, we examined plasma ACTH and cortisol responses to the competitive glucocorticoid antagonist RU 486 (10 mg/kg, p.o. at 8.00 h) versus placebo (PBO) in 7 healthy female volunteers and 8 patients with DSM-III-R anorexia nervosa, all of whom were studied while underweight [64.3 +/- 2.1% average body weight (ABW), mean +/- SE] and 5 of whom were restudied longitudinally following refeeding (> or = 85% ABW, mean 87.4 +/- 0.4% ABW). Blood samples were obtained from 16.00 to 16.30 h and from 4.00 to 8.00 h following dosing. Underweight anorexics were significantly hypercortisolemic by 24 h urinary free cortisol excretion compared with controls (239 +/- 37 vs. 119 +/- 12 nmol/day, p < 0.01). Both controls and underweight anorexics had robust early morning (4.00-8.00 h) plasma cortisol responses to RU 486 (465 +/- 61 and 719 +/- 49 nmol/l) compared with PBO (370 +/- 52 and 451 +/- 31 nmol/l; p < 0.02 and p < 0.01, respectively). The underweight anorexics showed a significant mean early morning plasma ACTH response to RU compared with placebo (3.28 +/- 0.63 vs. 2.01 +/- 0.24 pmol/l, p < 0.05), while the controls showed a trend toward an increase in mean plasma ACTH after RU (3.11 +/- 0.36 pmol/l) compared with PBO (2.31 +/- 0.41 pmol/l, p < 0.13); plasma ACTH means were greater on the RU day than the placebo day at 20 of 25 sampling points (p < 0.001). However, the increment in ACTH on the RU day compared to the placebo day was greater in the underweight anorexics at the first 20 of 25 consecutive time points of the early morning sampling period (p < 0.001). Moreover, underweight anorexics showed a significant plasma ACTH and cortisol response to RU 486 at 16.00-16.30 h (8-8.5 h following administration), while the controls showed no significant response of plasma ACTH or cortisol at this time. When restudied following weight recovery, anorexic patients showed reductions in 24-hour urinary free cortisol excretion (to 191 +/- 40 nmol/day) which were no longer significantly elevated compared with control values.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression.

The authors measured CSF concentrations of corticotropin-releasing hormone (CRH) and arginine vasopressin in nine depressed patients before and after fluoxetine treatment. They found significant decreases in CSF CRH, CSF arginine vasopressin, and Hamilton depression ratings. Thus, the therapeutic effect of this serotonin-uptake inhibitor may be related to diminution of these arousal-promoting neuropeptides.

Adult↗
PubMed1992

Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: preliminary findings.

The syndrome of chronic fatigue, feverishness, diffuse pains, and other constitutional complaints, often precipitated by an acute infectious illness and aggravated by physical and emotional stressors, has a lengthy history in the medical literature. The Centers for Disease Control (CDC) recently formulated a case definition, renaming the illness "chronic fatigue syndrome." Nevertheless, there remain few biological data that can validate the existence of this syndrome as distinct from a wide variety of other, largely psychiatric disorders, and little understanding of its pathogenesis. In the present study, basal plasma and cerebrospinal fluid levels of the monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) were determined in 19 patients meeting CDC research case criteria for chronic fatigue syndrome and in 17 normal individuals. Patients with chronic fatigue syndrome showed a significant reduction in basal plasma levels of MHPG and a significant increase in basal plasma levels of 5-HIAA. Although the functional significance of these findings has not been definitively elucidated, they are compatible with the clinical presentation of a syndrome associated with chronic lethargy and fatigue, and with evidence of persistent immune stimulation, and lend support to the idea that chronic fatigue syndrome represents a clinical entity with potential biological specificity.

Adult↗
PubMed1992

Effect of m-chlorophenylpiperazine on plasma arginine-vasopressin concentrations in healthy subjects.

It has been demonstrated convincingly that ACTH and prolactin release are under the stimulatory control of serotonin (5-hydroxytryptamine, 5HT). Recent animal studies suggest that stimulation of 5HT activity also induces the release of arginine-vasopressin (AVP). More specifically, m-chlorophenylpiperazine (MCPP), a 5HT agonist widely used to examine 5HT receptor responsivity in human subjects, has been found to induce AVP release in rodents. This study examined whether MCPP increased plasma AVP levels in healthy human subjects. MCPP was administered orally to 17 healthy subjects in a placebo-controlled design in doses of 0.25 and 0.5 mg/kg. AVP was measured twice hourly over a 210 min period after administration of capsules. MCPP did not significantly alter AVP levels as compared to placebo. However, female subjects had significantly lower plasma AVP levels than males. Since it has been suggested that MCPP-induced AVP release in animals is due to stimulation of 5HT1c receptors, the fact that MCPP did not induce the release of AVP in humans suggests that either MCPP is not a potent 5HT1c agonist or that AVP is not released by stimulation of 5HT(1c) receptors in human subjects. The observation of gender differences in plasma AVP levels suggests that this factor should be taken into account in future studies of AVP secretion in plasma.

Adult↗
PubMed1992

Central hypothyroidism is associated with advanced age in male Fischer 344/N rats: in vivo and in vitro studies.

We investigated age-related alterations in hypothalamic-pituitary-thyroid function in a series of in vivo and in vitro studies in 2-, 8-, 18-, and 24-month-old male Fischer 344/N (F344/N) rats. Thyroid histology showed progressive follicular loss with advancing age; this was associated with significant and progressive decrements in plasma levels of free T4 and free T3, but not immunoreactive TSH, which remained unchanged with age. This was accompanied by a progressive age-dependent loss in in vivo responsivity of the thyrotroph to synthetic TRH and a paradoxically augmented response of GH to this peptide in the oldest rats. Steady state levels of prepro-TRH mRNA in the hypothalamic paraventricular nucleus were decreased with age, whereas TRH content in and in vitro secretion by whole hypothalami remained unchanged. Both anterior pituitary steady state TSH beta-subunit mRNA levels and TSH content were decreased with age. Taken together, these data suggest that aging in male F344/N rats is associated with a progressive, centrally mediated decrease in thyroid function. The relative contributions to this phenomenon of age-related alterations in supra-hypothalamic and/or hypothalamic vs. pituitary thyrotropic function remain to be determined, as do the relationships between changes in hypothalamic-pituitary-thyroid function and those in aging per se.

Aging↗
PubMed1992

Effects of carbamazepine on pituitary-adrenal function in healthy volunteers.

Carbamazepine (CBZ) is a widely used therapeutic agent in seizure, pain, and mood disorders. Although CBZ has been shown to inhibit hypothalamic CRH secretion in vitro, limited data suggest that systemic CBZ induces pituitary-adrenal activation. Few data are available to reconcile these effects or clarify their mechanism(s), particularly in healthy human subjects. We report here a study of basal ACTH and cortisol secretion and their responses to ovine CRH administration in nine healthy volunteers, studied both during repeated (2-3 weeks) administration of CBZ and while medication free. CBZ significantly increased mean 24-h urinary free cortisol (mean +/- SE, 197 +/- 17 vs. 137 +/- 24 nmol/day; P less than 0.02) and evening basal total plasma cortisol (113 +/- 17 vs. 83 +/- 14 nmol/L; P less than 0.05) as well as cortisol-binding globulin-binding capacity (497 +/- 36 vs. 433 +/- 28 nmol/L; P less than 0.01). Despite the CBZ-induced hypercortisolism, plasma ACTH responses to CRH during CBZ treatment remained robust, rather than being suppressed by basal hypercortisolism. In fact, during CBZ treatment, we noted a positive correlation between the increase in basal plasma cortisol and the increase in the plasma ACTH response to CRH (r = 0.65; P less than 0.05). We also observed a reduction in cortisol-binding globulin-binding capacity after CRH administration (315 +/- 25 vs. 433 +/- 28 nmol/L; P less than 0.001), which was accentuated by CBZ treatment (342 +/- 19 vs. 497 +/- 36 nmol/L; P less than 0.001; magnitude of fall, -155 +/- 22 nmol/L on CBZ vs. -118 +/- 11 nmol/L off CBZ; P less than 0.05). We conclude that CBZ increases plasma cortisol secretion in healthy volunteers independent of its effect on plasma cortisol-binding capacity. This pituitary-adrenal activation seems to reflect a pituitary, rather than a hypothalamic, effect of CBZ. Hence, despite CBZ-induced hypercortisolism, the ACTH response to CRH remained robust in direct proportion to the CBZ-induced rise in basal plasma cortisol. Thus, we propose that the increased cortisol secretion observed during CBZ treatment reflects a relative inefficacy of glucocorticoid negative feedback at the pituitary. This pituitary-driven increase in cortisol secretion combined with the expected reduction in centrally directed CRH secretion could contribute to the anticonvulsant properties of CBZ.

Adrenocorticotropic Hormone↗
PubMed1991

Clinical and biochemical aspects of depressive disorders: I. Introduction, classification, and research techniques.

The present review focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. In addition to integrating these data, problems and future directions in this research are discussed. The review is presented in three parts. This study, Part I, describes diagnostic classification schemes for depressive disorders, some epidemiological and biological correlates of the classifications, and research techniques for investigating depressive disorders. Research techniques include animal models, human biochemical techniques, and Positron Emission Tomography. In a future issue, Part II will discuss various transmitter/receptor theories of depressive disorders, e.g., noradrenergic, serotonergic, cholinergic, and dopaminergic, GABAergic, and peptidergic theories. Also in a future issue, Part III will discuss treatments for depression and some of the controversies in the field.

Depressive Disorder↗
PubMed1991

Pituitary hormone responses to meta-chlorophenylpiperazine in panic disorder and healthy control subjects.

The present study reports adrenocorticotropic hormone (ACTH) and prolactin responses after oral administration of 0.25 mg/kg of the serotonin agonist, meta-chlorophenylpiperazine (MCPP), in patients with panic disorder (PD) and in healthy subjects. MCPP blood levels were similar for the two groups, but almost twice as high in males as in females. Female patients had augmented ACTH and prolactin release as compared to healthy females, while ACTH and prolactin release in male patients was similar to that of male controls. These results suggest that female PD patients have hypersensitive serotonin receptors. Moreover, they indicate that pharmacokinetic gender differences may affect challenge studies, and that different doses may be required to study neuroendocrine responses in males and females.

Adrenocorticotropic Hormone↗
PubMed1991

Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing's disease and major depression: potential clinical implications.

To explore whether possible differences in central nervous system neuromodulators contribute to the differential presentation of affective symptomatology in Cushing's disease and major depression, we examined the levels of immunoreactive CRH and ACTH in the cerebrospinal fluid (CSF) of 11 patients with Cushing's disease, a patient with ectopic ACTH secretion, 34 patients with major depression, and 60 healthy subjects. We elected to measure these peptides not only because both are classically involved in pituitary-adrenal regulation, but also because their primarily arousal-producing and anorexigenic behavioral effects in experimental animals suggest that they may play a role in the symptom complex of depressive syndromes. We also explored whether the CSF levels of these peptides were more helpful in determining the often difficult differential diagnosis between major depression and Cushing's disease than the plasma ACTH response to ovine CRH, a currently used but somewhat insensitive laboratory means of distinguishing these disorders. CSF levels of immunoreactive CRH and ACTH were significantly lower in Cushing's disease patients [21.9 +/- 2.7 and 15.4 +/- 1.8 pg/mL, (mean +/- SEM), respectively] compared to patients with major depression [38.4 +/- 2.3 pg/mL (P less than 0.01) and 24.5 +/- 1.6 pg/mL (P less than 0.01), respectively] and controls [38.4 +/- 1.6 pg/mL (P less than 0.001) and 26.3 +/- 1.1 pg/mL (P less than 0.001), respectively]. The coexistence of high plasma ACTH and low CSF ACTH in Cushing's disease yielded a CSF/plasma ACTH ratio consistently less than that in depressed patients, with only 2 of 31 subjects comprising both groups showing values that overlapped. In contrast, 9 of the combined patients showed ACTH responses to ovine CRH that overlapped. These data suggest that differences in centrally directed CRH secretion may account for the differential presentation of the dysphoric syndromes seen in major depression and Cushing's disease. Hence, the classic form of major depression (melancholia), is often associated with evidence of pathological hyperarousal, such as intense anxiety, sleeplessness, and anorexia, while that of Cushing's disease is associated with evidence of pathological hyperarousal, including hyperphagia, fatigue, and inertia. Moreover, measurement of the CSF/plasma ACTH ratio may serve as a clinically useful adjunct to the ovine CRH stimulation test and other laboratory measures in determining the differential diagnosis between major depression and Cushing's disease.

Adolescent↗
PubMed1990

Prednisone effects on neurochemistry and behavior. Preliminary findings.

To evaluate the neurochemical, neuroendocrine, and behavioral effects of exogenous corticosteroids in humans, we administered prednisone (80 mg/d orally for 5 days) in a double-blind manner to 12 medically healthy volunteers. Behavioral measures were assessed before, during, and after prednisone administration in all 12 subjects, and cerebrospinal fluid biochemistry was assessed before and during prednisone administration in 9 of the subjects. Prednisone administration was associated with decreases in cerebrospinal fluid levels of corticotropin, norepinephrine, beta-endorphin, beta-lipotropin, and somatostatinlike immunoreactivity. No significant changes were noted in cerebrospinal fluid levels of alpha-melanocyte-stimulating hormone, corticotropin-releasing hormone, 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, or 5-hydroxyindoleacetic acid. No consistent or significant group mean changes were observed in structured behavioral ratings, although 9 (75%) of the volunteers studied reported mild behavioral changes while receiving prednisone. Correlations between the neurochemical and behavioral changes are discussed.

Adult↗