COMPARISON OF THE STRUCTURAL FEATURES OF CORTICOTROPIN REQUIRED FOR STIMULATION OF STEROIDOGENESIS AND cAMP PRODUCTION IN RAT AND RABBIT ADRENOCORTICAL CELLS

The steroidogenic activities of ACTH, α-MSH, β-MSH as well as analogs of the hormones have been compared in rat and rabbit adrenocortical cells. ACTH is equally active in both species and the melanotropins have very low steroidogenic potency in either species. The steroidogenic potencies of the peptide analogs are strikingly similar in the two species, suggesting that the structural requirements for eliciting steroidogenesis are the same in rat and rabbit adrenocortical cells. The analog NPS-ACTH has low, comparable steroidogenic activity in both species. NPS-ACTH is a potent antagonist of ACTH-induced cAMP production in rat adrenocortical cells but acts as a weak partial agonist in rabbit adrenocortical cells. These results suggest that steroidogenesis may be mediated by receptors different from those involved in the cAMP response observed at supraphysiological concentrations of ACTH.     

Some effects of ACTH 4-10 on performance during a serial reaction task

Eighteen subjects worked continuously for half an hour in a self-paced reaction task. Half of the subjects were injected with ACTH 4–10 (30 mg/s.c.) and the other half with a placebo.The subjects injected with ACTH 4–10 showed a larger improvement in reaction time during the experimental session than the placebo group. However, this effect disappeared in a short retest, which was given half an hour after the experimental session.These results suggest that ACTH 4–10 has no effect on skill acquisition, but counteracts the build-up of reactive inhibition during the experimental session; that is, the peptide suppresses the decrease in motivation, which usually occurs during continuous performance tasks.This notion is confirmed by an analysis of the frequency distributions of the reaction times. Treatment effects were only found for the long reaction times. Long reaction times tend to occur with increasing frequency as a function of time-on-task and are an indication for the level of motivation of the subject.It was concluded that ACTH 4–10 counteracts the usual decay in performance as a function of time-on-task due to increasing boredom and mental fatigue.This study was supported by N. V. Organon.     

Modulation of brain polyphosphoinositide metabolism by ACTH and β-endorphin: Structure-activity studies

This study describes effects of ACTH_1–24 and β-endorphin on brain polyphosphoinositide metabolism in vitro. The interconversion of these polyanionic phospholipids was studied by incubation of a lysed synaptosomal fraction with [γ-³²P]ATP. Of the membrane phospholipids only PA, DPI and TPI became labeled. The reference peptide ACTH_1–24 stimulated the formation of TPI and inhibited the production of PA. For effects on TPI formation both the sequences ACTH_5–7 and ACTH_10–16 were needed. Effects of PA formation required the sequences ACTH_7–10 and ACTH_10–16. The basic amino acids in ACTH_10–16 seemed to be of crucial importance for the peptide effects. A stimulatory effect on DPI was visible when ACTH was shortened from the N-terminus, and the essential information was in ACTH_7–10. β-endorphin inhibited PA formation and this effect was abolished by C-terminal shortening to γ-endorphin. Other fragments of the C-terminus of β-LPH, including the enkephalins, were ineffective. It is concluded that the structure-activity relationship obtTPI/PA formation correlates with a similar relationship obtained on excessive grooming behavior in vivo. A possible correlation between the effects on polyPI metabolism and opiate-like effects, and effects on extinction of active avoidance behavior in vivo is discussed.     

Biological correlates of attachment bond disruption in humans and nonhuman primates

Separations or disruptions in attachment bonds occur frequently in the social lives of humans and have been linked to the development of psychopathology. Separation of social nonhuman primates has been proposed as a model to study the psychological and biological effects of separation in humans. This paper reviews the biological alterations that occur in nonhuman primates undergoing separation and compares these with changes associated with separation in humans. The data reviewed demonstrate that separation in humans and nonhuman primates can be an event with profound behavioral and physiological sequelae.     

Pregnenolone biosynthesis in isolated cells of Snell rat adrenocortical carcinoma 494.

Adrenocorticotrophin (ACTH) produced an insignificant stimulation of pregnenolone biosynthesis from endogenous precursors in isolated cells prepared from the rat Snell adrenal carcinoma 494. On the addition of 25-hydroxycholesterol, the rate of pregnenolone synthesis increased 10-fold. These results, noting also the very low cholesterol content of the tumor cells, suggested that lack of cholesterol was responsible for the poor steroidogenic response of the cells to ACTH. Endogenous pregnenolone production was sensitive to cytochalasin B as well as cycloheximide. However, pregnenolone synthesis after the addition of 25-hydroxycholesterol was not affected by these inhibitors. Removal of cycloheximide from the cells resulted in the immediate restoration of the initial rate of pregnenolone synthesis from endogenous precursors. This suggested that cycloheximide was interfering with the action of a stable activated intracellular messenger.     

In vitro secretion of pro-opiomelanocortin (POMC) derived peptides in human ACTH-producing pituitary adenomas: evaluation of hormone ratios in different functional states

In 14 cases of ACTH-producing pituitary adenomas (8 cases of Cushing's disease and 6 cases of Nelson's syndrome) dispersed cells prepared from adenoma tissue were incubated in a superfusion or static incubation system and investigated for ACTH, beta-endorphin (beta-EP) and beta-lipoprotein (beta-LPH) production. Effects of cortisol and lysine vasopressin (LVP) were evaluated. During the superfusion a qualitatively parallel secretory pattern is obtained for all hormones. Quantitatively, however, the response to LVP stimulation is more pronounced for beta-endorphin-like immunoreactivity (beta-LPH/beta-EP-IR) causing ACTH/beta-LPH/beta-EP-IR ratios to change throughout single experiments. beta-EP/beta-LPH ratios, however, which were estimated by means of Sephadex G-50 gel chromatography at various key points of the superfusion, were constant for each tumor, although variable between different adenomas, ranging from 0.68 to 2.0. The results suggest neither a differential control for the secretion of the peptides investigated within individual tumors nor a direct effect of cortisol or LVP on pro-opiomelanocortin processing. Summarizing clinical data and in vitro findings such as secretory behavior or hormone ratios, we can find no characteristic differences between Nelson's syndrome and Cushing's disease.     

Dopamine involvement in ACTH-induced grooming behavior

Low doses of dopamine agonists and antagonists were tested for their effects on the excessive grooming behavior induced by intracerebroventricular (ICV) injections of ACTH1-24. Grooming scores were significantly depressed at doses of haloperidol, metoclopramide, pimozide, and butaclamol that did not decrease locomotor activity. In fact at two doses of haloperidol (0.067 and 0.10 mg/kg), grooming scores were decreased while locomotor activity was increased significantly. Metoclopramide increased grooming scores at a dose reported to block presynaptic dopamine receptors. Apomorphine potentiated the grooming induced by low doses of ACTH. These data support the hypothesis that dopaminergic neurotransmission is necessary for the display of ACTH-induced grooming behavior.     

Regulation der Plasmaaldosteronkonzentration bei nierenlosen Patienten

Zusammenfassung Bei 14 anephrischen Patienten wurde der Einfluß von ACTH, Angiotensin II, Orthostase und Hämodialyse auf die Plasmaaldosteronkonzentration untersucht. Gleichzeitg wurden Plasmareninaktivität (PRA), Plasmacortisol, Serumnatrium und Serumkalium bestimmt.Unter 4stündiger Infusion von synthetischem ACTH (2,5 µg/min Synachten) kam es zu einem signifikanten Anstieg des Plasmaaldosterons und des Plasmacortisols (p<0,025 bzw. <0,005), während Serumnatrium und Serumkalium unverändert blieben.Eine einstündige Infusion einer suppressorischen Dosis von synthetischem Angiotensin II (1,0 ng/kg Körpergewicht/min Hypertensin) führte zu einem geringgradigen, jedoch nicht signifikanten Anstieg des Plasmaaldosterons und hatte keinen Einfluß auf Plasmacortisol und Serumelektrolyte. Eine nach 60 min zusätzlich durchgeführte ACTH-Infusion (2,5 µg/min Synacthen) bewirkte über einen Zeitraum von 4 h einen ähnlichen Plasmaaldosteronansteig wie die alleinige ACTH-Infusion.Durch Orthostase ließ sich ein signifikanter Anstieg des Plasmaaldosterons (p<0,05) erzielen, während Plasmacortisol und Serumelektrolyte keine signifikanten Veränderungen zeigten.Sowohl normale als auch isonatriämische und isokaliämische Hämodialyse führten zu einem vergleichbaren Anstieg des Plasmaaldosterons. Das Plasmacortisol blieb bei der normalen Hämodialyse unverändert und fiel bei der isonatriämischen und isokaliämischen Hämodialyse ab.Die Plasmareninaktivität war unter den beschriebenen Versuchsbedingungen mit ganz wenigen Ausnahmen nicht meßbar (<0,2 mg/ml·3 h). Vereinzelt tiefnormale PRA-Werte wurden weder durch Hämodialyse noch Orthostase beeinflußt.Unsere Ergebnisse zeigen bei nierenlosen Patienten eine Stimulation des Plasmaaldosterons durch synthetisches ACTH, ein geringgradiges Ansprechen auf suppressorisches Angiotensin II, eine fehlende Potenzierung der ACTH-Wirkung durch suppressorische Dosen von Angiotensin II und einen Aldosteronanstieg unter Orthostase. Ferner ließ sich unter Hämodialyse ein Anstieg des Plasmaaldosterons beobachten. Dieser Anstieg trat sowohl unter normaler als auch unter isokaliämischer und isonatriämischer Hämodialyse auf und konnte deshalb ebenso wie die durch Orthostase induzierte Veränderung der Hormonkonzentration keinem der bekannten aldosteronstimulierenden Faktoren zugeordnet werden. Eine mögliche Beteiligung anderer Faktoren an der Aldosteronregulation ist deshalb anzunehmen.     

Beta-endorphin/ACTH immunocytochemistry in the CNS of the lizard Anolis carolinensis: evidence for a major mesencephalic cell group

The immunocytochemical distribution of beta-endorphin and other proopiomelanocortin (POMC) peptides in the central nervous system of the lizard Anolis carolinensis was determined. Colchicine pretreatment was used to enhance perikaryal immunoreactivity. A major finding of this study is the localization of a previously undetected mesencephalic cell group which exhibits immunoreactivity to beta-endorphin, ACTH, and alpha-MSH. The perikarya of these neurons are large, bipolar, and situated in the mesencephalic tegmental area. They appear to project to the mesencephalic central gray and other brainstem structures. In contrast, the immunoreactive parvicellular perikarya of the medial-basal hypothalamus, corresponding to the POMC perikarya of the rodent arcuate nucleus, exhibit major rostral projections to various telencephalic and diencephalic structures. The exact extent of fiber projections and innervation patterns arising from either of these two groups is not clear at this time and will require further analyses. Scattered fiber immunoreactivity was also seen in the medial cerebral cortex and the striatal complex, regions which apparently are not innervated by beta-endorphin fibers in the rodent brain. Also, no immunoreactivity was seen to an antiserum to the 16K peptide of POMC. Other similarities and differences in the brain distribution of POMC in reptiles and mammals are discussed.     

Adrenocortical responses to ether stress and neural stimuli in rats following the injection of 6-hydroxydopamine into the medial forebrain bundle

Adrenocortical responses, as expressed by changes in plasma corticosterone concentrations, after ether stress, or photic, acoustic, or sciatic nerve stimulation were studied in rats, with 6-hydroxydopamine or vehicle injected into the medial forebrain bundle (MFB). The neurotoxin partially inhibited the response to photic stimulation only, indicating the involvement of MFB catecholaminergic fibers in the transmission of this response which stimulates adrenocortical secretion.