Apolipoprotein E epsilon 4.
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Age of Onset↗
Biomedical subjects
J C Ritchie
Publications and source records attributed to J C Ritchie.
Cortisol responses following placebo and alcohol in Asians with different ALDH2 genotypes.
Alcohol-induced flushing occurs in Asians who possess ALDH2*2 alleles. This study genotyped 30 Asian American men for ALDH2 and evaluated them on two separate occasions where they received in random order placebo and 0.75 ml/kg alcohol. Blood samples were drawn at baseline and 15, 30, 60, 90, 120 and 150 minutes after beverage administration for subsequent estimation of blood alcohol and plasma cortisol levels. Subjects with ALDH2*2 alleles demonstrated significantly higher cortisol levels after alcohol consumption than subjects with ALDH2*1/2*1 genotype, despite equivalent blood alcohol concentrations. One subject who was homozygous for ALDH2*2 had extraordinarily high cortisol levels at 90, 120 and 150 minutes after alcohol. These data are consistent with the hypothesis that Asians with ALDH2*2 alleles, who flush after drinking, experience more intense reactions to alcohol than nonflushing Asians with ALDH2*1/2*1 genotype.
Adult↗
The dexamethasone suppression test and quantitative cerebral anatomy in depression.
To determine whether structural brain abnormalities in patients with depression are related to cortisol state, we examined the relationship between the dexamethasone suppression test (DST) and brain magnetic resonance imaging (MRI) in 40 inpatients with severe depression referred for electroconvulsive therapy (ECT). Prior to ECT, 27 (68%) of the patients exhibited nonsuppression on the DST. Frontal lobe volume was negatively correlated with peak post-dexamethasone cortisone (r = -0.37) and was 13% smaller in DST nonsuppressors than suppressors; these findings were no longer significant after adjustments for age, gender, and cranial size. Lateral and third ventricular volumes were also correlated with peak postdexamethasone cortisol (r = 0.34 and 0.33, respectively), but not after adjustments for age, gender, and cranial size. Subcortical hyperintensity was associated with peak postdexamethasone cortisol and was more common in DST nonsuppressors than suppressors. Again these findings were no longer significant after adjustments for age. Finally, longitudinal DST and brain MRI studies in 11 of these patients revealed no changes in regional brain volumes nor in postdexamethasone cortisol up to six months after ECT. However, within individual patients, postdexamethasone cortisol was positively (and significantly) correlated with frontal lobe volume.
Adult↗
Dose response relationship between plasma ACTH and cortisol after the infusion of ACTH1-24.
The authors examined the dose response relationship between plasma ACTH and cortisol concentrations after the administration of various doses of ACTH1-24 (0.025 micrograms, 0.125 micrograms, 0.25 micrograms, 1 microgram, 250 micrograms) in dexamethasone-suppressed normal volunteers. A logarithmic dose-response relationship between the dose of ACTH administered and plasma cortisol concentration was found. Although there was considerable variability in plasma ACTH concentrations, there was, however, a definite correlation between area under the curve for ACTH and area under the curve for cortisol after the various doses of ACTH.
Adrenocorticotropic Hormone↗
Preliminary studies of 6 beta-hydroxydexamethasone and its importance in the DST.
The role of the metabolites of dexamethasone (DEX) in the dexamethasone suppression test (DST) has never been fully elucidated. We report here our preliminary studies of 6 beta-hydroxydexamethasone (6 OH-Dex), a known metabolite of DEX, on the hypothalamic-pituitary-adrenal (HPA) axis of the rat; its activity in the most commonly used radioimmunoassay for plasma DEX; and its plasma concentrations in a normal human subject during the standard 1.0 mg DST. Six OH-Dex administered subcutaneously to rats at a dose of 1 mg/kg was able to completely suppress corticosterone production for at least 3 hr. In the IgG Corp. radioimmunoassay for plasma DEX, 6 OH-Dex was moderately cross-reactive yielding a 50% cross-reactivity of 10%. Gas chromatographic coupled mass spectroscopic analysis of human plasma samples, obtained 12 to 20 hr after the oral ingestion of 1.0 mg DEX, demonstrated similar plasma concentrations for both the parent compound and the 6-hydroxyl metabolite. The relevance of these findings, particularly to pharmacokinetic studies of the DST, is discussed.
Animals↗
5 alpha-pregnane-3 alpha, 21-diol-20-one (THDOC) attenuates mild stress-induced increases in plasma corticosterone via a non-glucocorticoid mechanism: comparison with alprazolam.
5 alpha-Pregnane-3 alpha,21-diol-20-one (THDOC; 5 mg/kg) and the triazolobenzodiazepine alprazolam (1 mg/kg) attenuated mild stress-induced increases in plasma corticosterone concentrations via GABAergic mechanisms. Unlike alprazolam, THDOC failed to decrease corticotropin-releasing factor (CRF) concentrations in the locus ceruleus. While THDOC may plausibly act via endogenous GABAergic mechanisms to reduce stress-induced endocrine and behavioral responses that are likely mediated in part by CRF neurons, these preliminary findings suggest that, at the dose and time point studied, THDOC does not identically mimic the actions of alprazolam, another drug which potentiates GABAergic activity.
Alprazolam↗
Modeling the pharmacokinetics and pharmacodynamics of dexamethasone in depressed patients.
Changes in time course effected by cortisol suppression and the relationship of these changes to the plasma dexamethasone concentration of suppressor and non-suppressor patients are described in this report on a combined pharmacokinetic-pharmacodynamic model. Thirteen depressed patients (8 suppressors and 5 non-suppressors) received an intravenous dose (1.5 mg) of dexamethasone. The drug-induced effect changes are found to lag behind, in time, the plasma drug level changes. To accurately relate the temporal relationship of effect changes to plasma dexamethasone levels, a pharmacodynamic model (sigmoid-Emax) was combined with a pharmacokinetic model that incorporated an effect compartment. The magnitude of the time-lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma dexamethasone levels (t1/2keo). The t1/2keo of the nonsuppressing group was about 50% of that of the suppressing group, indicating that for a given plasma level the onset and termination of effect for the nonsuppressing group is about two times more rapid than for the suppressing group. Moreover, the model can estimate the effect-site concentration that causes one-half of the maximal predicted effect (EC50), a measure of an individual's sensitivity to dexamethasone. The receptor sensitivity (as determined from the EC50 ratio) of the suppressing group was about twice that of the nonsuppressing group.
Depression↗
In vivo assessment of pituitary volume with magnetic resonance imaging and systematic stereology: relationship to dexamethasone suppression test results in patients.
The relationship between dexamethasone suppression test (DST) results and in vivo pituitary volume was studied in 24 psychiatric inpatients. The principles of systematic stereology were used to measure pituitary volume from 3-mm contiguous sagittal spin-echo magnetic resonance (MR) images of the brain. There was no correlation between pituitary volume and 3 p.m. or 10 p.m. postdexamethasone (post-DEX) plasma cortisol concentrations. However, when multiple regression analysis was performed to relate pituitary volume to gender, age, and post-DEX plasma cortisol concentrations, there was a significant relationship between pituitary volume and age, gender, and 10 p.m. post-DEX cortisol plasma concentration. This is the first study to demonstrate a method that directly measures, rather than estimates, in vivo pituitary volume. Furthermore, it suggests that activation of the hypothalamic-pituitary-adrenal axis in psychiatric patients, as manifested by elevated post-DEX cortisol concentrations, may influence pituitary volume.
Adult↗
RU486 in depression.
RU486 is a synthetic glucocorticoid antagonist. The authors used RU486 to examine the hypothesis that the elevated plasma cortisol and ACTH in patients is due to suprahypophyseal stimulation of the anterior pituitary. Seven patients and matched controls were studied before and after the administration of RU486. RU486 produced an increase in HPA activity in depressed patients. Thus providing support for the hypothesis that there is increased suprahypophyseal stimulation of the anterior pituitary.
Adrenocorticotropic Hormone↗
Human immunodeficiency virus glycoprotein (gp120) infused into rat brain induces interleukin 1 to elevate pituitary-adrenal activity and decrease peripheral cellular immune responses.
Intracerebroventricular (i.c.v.) infusion of glycosylated recombinant gp120, the envelope protein of human immunodeficiency virus, in various doses (100 ng to 4 micrograms) resulted in detection of interleukin 1 (IL-1) activity in a high percentage (61%; 33 of 54) of rat brains, whereas IL-1 was very rarely detected in brains of animals infused with several control substances (4%; 1 of 28). To detect IL-1, clarified glial lysate of diencephalon plus brainstem was subjected to gel exclusion chromatography and fractions were assessed for thymocyte stimulation. IL-1 was seen 2, 6, and 24 hr postinfusion. i.c.v. gp120 also produced known effects of IL-1 in brain, elevating steroid concentration in plasma and decreasing cellular immune responses [natural killer (NK) cell activity and mitogenic response to Con A] of blood and splenic lymphocytes. When gp120 was infused together with alpha-melanocyte-stimulating hormone (20 ng), which blocks many biological actions of IL-1, gp120 no longer elevated steroids or decreased NK cell activity. After intravenous gp120, IL-1 was not found in brain or plasma, indicating that stimulation of IL-1 in brain by i.c.v. gp120 was not due to gp120 affecting infiltrating cells from blood or to elevated circulating IL-1. That induction of IL-1 in brain might have resulted from lipopolysaccharide (LPS) in the gp120 solution was ruled out by studies showing that (i) heating of the infusion solution, which does not affect the capacity of LPS to induce IL-1, eliminated the ability of gp120 infusion to induce brain IL-1, and (ii) gp120 induced IL-1 in brains of LPS-resistant C3H/HeJ mice. Injection of gp120 directly into the hippocampus stimulated IL-1 more readily than i.c.v. infusion. Thymocyte stimulation produced by active fractions of gp120-infused brains was blocked by monoclonal antibody to IL-1 receptors. These findings indicate that elevation of IL-1 in brain can result from infection with human immunodeficiency virus and may be responsible for certain abnormalities (e.g., elevated activity of pituitary-adrenal axis) seen in AIDS patients.
Animals↗
Effects of interleukin-1 infused into brain are antagonized by alpha-MSH in a dose-dependent manner.
Interleukin-1 (IL-1) in the brain stimulates the pituitary-adrenal axis and markedly suppresses cellular immune responses. alpha-Melanocyte-stimulating hormone (alpha-MSH) introduced into the ventricular system simultaneously with IL-1 blocked these effects of IL-1 in a dose-dependent manner, with 10 ng of alpha-MSH totally blocking the elevation of plasma ACTH and corticosterone and suppression of Natural Killer (NK) cell activity produced by a dose of IL-1 (100 pg) that otherwise causes maximal effects. In that IL-1 has been shown to promote production of alpha-MSH, these results suggest that actions of IL-1 in brain are under negative feedback control and, consequently, that the effects of this cytokine in brain are of biological significance.
Adrenocorticotropic Hormone↗
Muscimol injections into the median raphe nucleus increase serum ACTH and corticosterone concentrations via a nonserotonergic mechanism.
Midbrain raphe serotonin (5-HT) neurons can influence the pituitary-adrenal axis. The midbrain raphe nuclei also contain a number of non-5-HT neurons, including gamma-aminobutyric acid (GABA) interneurons which can modulate 5-HT neuronal activity. We investigated the effects of intraraphe injections of the GABAA agonist, muscimol, on serum adrenocorticotropin hormone (ACTH) and corticosterone concentrations. Rats were infused with muscimol (0, 25, 50, and 100 ng in 0.5 microliters saline) into the median raphe nucleus (MR). The animals were killed 30 min later, and trunk blood was collected for measurement of serum concentrations of ACTH and corticosterone by radioimmunoassay. Muscimol dose dependently increased plasma concentrations of these two pituitary-adrenal hormones. In order to determine the role of MR 5-HT neurons in these effects, separate groups of implanted animals were infused with either the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) or ascorbic acid vehicle into the MR. Two weeks later, the animals were infused with muscimol (100 ng in 0.5 microliters) and sacrificed as above. Treatment with 5,7-DHT, which markedly reduced hippocampal concentrations of 5-HT (-83%) and 5-HIAA (-73%), did not block intra-MR muscimol-induced elevations in ACTH and corticosterone. Thus, 5-HT neurons within the MR apparently do not mediate the increased activity of the pituitary-adrenal axis produced by stimulation of MR GABAA receptors.
5,7-Dihydroxytryptamine↗
Fast feedback regulation of ACTH by cortisol.
1. Fast feedback regulation of ACTH by cortisol has not been well studied in humans. The authors studied the existence and characteristics of fast feedback regulation in normal humans. 2. Hydrocortisone hemisuccinate was infused at two different rates: 6 mg/hour and 12 mg/hour for two hours. 3. The studies did not demonstrate the existence of fast feedback regulation of basal ACTH concentration by cortisol in man. Further, the response was variable and the rate sensitive character was difficult to demonstrate.
Adrenocorticotropic Hormone↗
Role of serotonin in hypothalamo pituitary adrenal axis escape from dexamethasone suppression.
1. The authors investigated the role of serotonin in the hypothalamo pituitary adrenal escape from depression. 2. Maximal dose of fenfluramine was administered to normal individuals pretreated with dexamethasone. 3. Fenfluramine had only a minimal and inconsistent effect on the hypothalamo pituitary adrenal axis in the presence of dexamethasone.
Adrenocorticotropic Hormone↗
Novel binding mode of highly potent HIV-proteinase inhibitors incorporating the (R)-hydroxyethylamine isostere.
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Enzyme Inhibitors↗
Levels of urinary free cortisol in social phobia.
Levels of urinary free cortisol were measured in 10 patients with social phobias and in 15 age- and sex-matched normal controls. No differences were found either in cortisol levels or in the ratio of free cortisol to creatinine. These nonsignificant differences between groups do not necessarily rule out the possibility that the hypothalamic-pituitary-adrenal axis may be altered in individuals with social phobia.
Adult↗
The 5-hydroxytryptamine2 agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. I. Acute effects on HPA axis activity and corticotropin-releasing factor-containing neurons in the rat brain.
Corticotropin-releasing factor (CRF) is the major physiological regulator of adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary. In vivo and in vitro studies have suggested that hypothalamic CRF secretion is under stimulatory serotonergic control, although the receptor subtype(s) responsible have not been definitely determined. The acute effects of the 5-hydroxytryptamine2 agonist, (+-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), were examined on a number of biochemical indices of hypothalamic-pituitary-adrenal axis activity in vivo. DOB increased plasma ACTH and corticosterone concentrations at doses greater than 0.1 mg/kg. This effect is dose-dependent. Peak effects occurred 30 min postinjection and returned to basal levels by 4 hr after DOB injection. These effects of DOB are hypothesized to be mediated by the release of hypothalamic CRF because pretreatment with the CRF receptor antagonist (alpha-helical CRF9-41) significantly attenuated the ACTH response to DOB. Median eminence CRF content was also decreased following DOB administration in the presence of the protein synthesis inhibitor, cycloheximide (200 mg/kg i.p.), suggestive of release of CRF from median eminence terminals as a result of DOB activation of CRF neurons. DOB administration was without effect on brain CRF concentrations in all of the 12 extrahypothalamic brain regions studied 60 min after injection. These results, taken together, support a stimulatory role for 5-hydroxytryptamine2 receptors on hypothalamic CRF secretion.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
The 5-hydroxytryptamine2 agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. II. Biochemical and physiological evidence for the development of tolerance after chronic administration.
In order to investigate the long term effects of the 5-hydroxytryptamine2 (5-HT2) receptor agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), on hypothalamic-pituitary-adrenal (HPA) axis activity, DOB (0.35 mg/kg/day) was administered via osmotic minipumps to rats for 7 days at which time plasma adrenocorticotrophic hormone (ACTH), corticosterone and regional brain corticotropin-releasing factor (CRF) concentrations were measured. In addition, anterior pituitary CRF and frontal cortical 5-HT2 receptor binding was measured. Seven-day infusion of DOB resulted in tolerance to the stimulatory actions of the drug on the HPA axis as evidenced by the return of plasma ACTH and corticosterone concentrations to base-line values. Moreover, rats treated chronically with DOB exhibited decreased numbers of both anterior pituitary CRF and cortical and hypothalamic 5-HT2 receptor. These receptor changes were physiologically significant as challenges doses of DOB or CRF resulted in blunted ACTH responses. Chronic DOB infusion was without effect on CRF concentrations in all hypothalamic and extrahypothalamic brain regions studied. A series of time course experiments revealed that DOB-induced increases in plasma corticosterone returned to base-line by 2-days postimplantation. This effect was apparently associated with down-regulation of the 5-HT2 receptor because high-affinity cortical [3H]DOB and hypothalamic (+-)-[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane binding were decreased at this time as well. Although median eminence CRF content was unchanged at all time points, anterior pituitary CRF receptor binding was significantly decreased 7 days postimplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
DOM 2,5-Dimethoxy-4-Methylamphetamine↗