Naltrexone-sensitive behavioral actions of the ACTH 4-9 analog (Org 2766)

The effects of the ACTH 4-9 analog (Org 2766) and the COOH-terminal tripeptide of Org 2766 (Phe-D-Lys-Phe; PDLP) on retrieval of one-trial learning passive avoidance behavior were compared with those of beta-endorphin, [Met5]-enkephalin, [D-Ala2,Met5]-enkephalin, des-Tyr1-[Met5]-enkephalin and des-enkephalin-gamma-endorphin (DE gamma E). Amounts of intracerebroventricularly administered Org 2766, PDLP, [Met5]-enkephalin, [D-Ala2,Met5]-enkephalin and DE gamma E, which induced a comparable attenuation of passive avoidance behavior were determined. Pretreatment with the opiate antagonist naltrexone prevented the attenuating effect of these peptides on passive avoidance behavior except that of DE gamma E. The attenuating effect of Org 2766 and of [Met5]-enkephalin was reversed to facilitation of passive avoidance behavior in the presence of naltrexone. Subcutaneous treatment with Org 2766 and [D-Phe7]-ACTH 4-10 decreased electrical self-stimulation behavior elicited from the medial septal area. Naltrexone prevented the inhibitory effect of Org 2766 on this behavior, but not that of [D-Phe7]-ACTH 4-10. Although the attenuating effect of PDLP on passive avoidance behavior was not reduced by pretreatment with [Met5]-enkephalin- or beta-endorphin-antiserum, and PDLP induced neither analgesia nor excessive grooming, the data suggest that the inhibitory effect of Org 2766 and PDLP on passive avoidance behavior and electrical self-stimulation are mediated by endorphin systems in the brain.     

An analog of MSH/ACTH 4–9 enhances interpersonal and environmental awareness in mentally retarded adults

In a double blind procedure, four doses (0, 5, 10 and 20 mg) of an orally active analog of ACTH/MSH 4–9 was administered to mentally retarded adults. Changes in behavior and in productivity were evaluated as subjects performed their job in a sheltered workshop. During the first week productivity suffered while behavior related to communication and sociability increased in clients receiving the peptide analog. During the second week, clients given the peptide were more productive and attentive to environmental events while differences in sociability stabilized. Five and 10 mg enhanced productivity of tasks requiring precision and concentration whereas 20 mg depressed performance of all tasks. Regression equations indicated that different doses of the peptide generated unique relationships between behavior and productivity with self-stimulation characterizing the clients given the peptide. The use of the peptide analog of ACTH/MSH as a potential treatment with the mentally retarded is encouraged by these findings.     

The effect of ACTH4-9 analog (Org2766) on some cerebrospinal fluid parameters in patients with Alzheimer's disease

In a double-blind, placebo-controlled study, the central nervous system effects of an ACTH4-9 analog, Org2766 (40 mg/day), in Alzheimer's disease were assessed by measuring cerebrospinal fluid parameters during 6 months' treatment. Somatostatin-like immunoreactivity and cholinesterase activity, which are known to be reduced in cerebrospinal fluid of Alzheimer patients compared with controls, did not change during treatment. As a marker of noradrenergic and dopaminergic systems, we measured dopamine-beta-hydroxylase and homovanillic acid, but both levels were static. These results suggest that Org2766 did not interact with the transmitter systems, which are thought to be disturbed in Alzheimer's disease.     

The MSH/ACTH(4-9) analog Org2766 counteracts isolation-induced enhanced social behavior via the amygdala.

MSH/ACTH-like peptides influence social behavior induced by isolation It has been previously demonstrated that changes in locomotor activity as a result of isolation can be counteracted by Org2766 via the amygdala. The present study investigates whether isolation-induced changes in social behavior can also be affected by this peptide via the amygdala. A fully automated observation system was applied for detailed registration and analysis of movements of group-housed and 7-day isolated rats in a social interaction test. Administration of the MSH/ACTH(4-9) analog into the central nucleus of the amygdala elicited decreased locomotion, approach, and avoidance behaviors after isolation as compared to placebo-treated controls. However, general activity and social interest of group-housed rats were not affected by the MSH/ACTH(4-9) fragment. It is hypothesized that the amygdala is a site of action for neuropeptides in modulating social behavior.     

The ACTH/MSH (4-9) analog Org2766 improves retrieval of information after a fimbria fornix transection

The fimbria fornix of male Wistar rats was transected unilaterally after they had been successfully trained in the Morris maze and the passive avoidance task. Sham-operated and lesioned animals were treated either with Org2766 or saline for two weeks. Subsequently, the performance of all groups was tested again starting two days after the last treatment. The lesioned animals showed a deficit in performance in both tasks, indicating interference of the lesion with retrieval of information. Org2766 improved the poor performance of the lesioned animals in the Morris maze, but not in the passive avoidance task.     

ACTH 4-9 effects on the human visual event-related potential

Three oral doses (5, 10 and 20 mg) of an analog of ACTH 4-9 were compared with a vehicle control and d-amphetamine (10 mg). In a double-blind procedure, five men and five women were tested at weekly intervals with each treatment. In each session, four visual event-related potentials (ERPs) were recorded at hourly intervals. Visual ERPs were averaged from the electroencephalogram recorded from the left and right hemisphere. Dosage, time after administration, hemisphere of the brain and sex of the subject influenced the ERP. The ACTH 4-9 analog decreased amplitude of P100 but increased integrated activity of the ERP. This effect peaked at 60 minutes then "recovered." The effects of the peptide were more pronounced with doses of 5 and 10 mg, in the right hemisphere of men and in the left hemisphere of women. The findings indicated that the ACTH 4-9 analog influenced components of ERP commonly related to the perceptual/attentional state of the organism in a sexually dimorphic manner.     

The effect of Hoe-427 (an ACTH4-9 analog) on free-choice ethanol consumption in male and female rats.

Ethanol consummatory patterns of individual male and female rats and the effects of Hoe-427 (Ebiratide), an ACTH4-9 analog, thereon, were studied in a test system using 24 hour, two-bottle free choice consumption between 0.2% saccharin and 10% ethanol in 0.2% saccharin. Single, daily i.p. doses (0.03mg/rat) of either ACTH4-10 or its analog resulted in a significant reduction of daily ethanol consumption with no effects on saccharin consumption. After 4 days of treatment, male rats consistently exhibited a rebound increase in ethanol consumption; this effect was not seen in females. The daily ethanol consummatory patterns of the female animals seemed to exhibit a 4-6 day cyclic rhythymicity, suggesting an interaction with estrous cycles. These results support a role for ACTH4-10 in the initiation of ethanol consummatory behavior in rats and suggests the existence of sex differences in this phenomenon.     

Chemico-enzymatic synthesis of an oligonucleotide template for an analog of ACTH (4-10) fragment

Six oligodeoxyribonucleotides ranging from 9-mer to 13-mer were synthesized in solution by the phosphotriester approach and enzymatically joined by T4 DNA ligase. The obtained double-stranded DNA (32 b.p.) with protruding 5'-ends corresponding to the recognition sites for restrictases EcoRI and BamHI represents an oligonucleotide template coding for the modified amino acid sequence 4-10 of the adrenocorticotropic hormone, [Pro8,Gly9,Pro10]ACTH-(4-10).     

Effect of (L-Phe7) and (D-Phe7) ACTH 4-7 and an ACTH 4-7 analog with prolonged action on acetylcholinesterase activity in the rat brain

ACTH4-7 and its long-acting analog stimulate acetylcholinesterase activity of different areas of the rat brain. Based on the data concerning the effect of an amino acid mixture equivalent to ACTH4-7 and actinomycin D on acetylcholinesterase activity of the white substance of the large hemispheres it is inferred that the oligopeptide-induced increase in the enzyme activity is linked with the induction of the synthesis of new acetylcholinesterase molecules.     

Effects of an ACTH/MSH(4-9) analog (HOE 427) on the sleep EEG and nocturnal hormonal secretion in humans.

The synthetic ACTH/MSH(4-9) analog HOE 427 ("ebiratide"), which is behaviorally the most potent ACTH-derived peptide but which is devoid of endocrine activity, was administered intravenously in a pulsatile mode 4 times (120 micrograms each) at 2200, 2300, 2400 and 0100 to study its effect on the sleep EEG and on concomitant hormonal secretion of cortisol and growth hormone. In comparison to placebo, the peptide produced signs of general activation associated with specific deteriorating effects on the quality of sleep. Sleep onset latency and intermittent wakefulness were increased, slow wave sleep was reduced, but only during the first 3 hours of the sleep period. The nocturnal secretory patterns of cortisol and growth hormone were unaffected by HOE 427. These effects are different from those reported in similar studies in which corticotropin-releasing hormone (CRH) was applied in humans, and they suggest that peripherally administered neuropeptides have specific nonendocrine behavioral effects.     

An emergent mechanism of selective visual attention in Drosophila

Due to the limited computational capacity of visual systems and the limited capacity to perform several mental operations at once, animals only select a small proportion of the stimuli available at any one time. It remains to be clarified how this process is related to the spatio-temporal dynamics of cell assemblies in the brain. By employing the flight simulator, selective visual attention behavior is studied in Drosophila. It has been found that for the visual objects presented, the tethered fruitflies display various attention patterns. Specifically, the learning memory mutants dunce and amnesiac possess attention patterns totally different from that of the wild-type fly. To explain these results from the viewpoint of dynamic cell assemblies, a neural network has been developed in which a possible link between the activity of cell assemblies, encoding of sensory information, and selective attention in Drosophila is proposed. Received: 3 November 1998 / Accepted in revised form: 1 July 1999     

Centrally administered N-terminal fragments of ACTH (1-10, 4-10, 4-9) display convulsant properties in rabbits

Electroencephalographic and behavioral effects of the following ACTH fragments: 1-4, 4-9, 4-11, 1-10, 4-10, 1-13, 1-17 and 1-24 were studied in rabbits. Sequences 4-9, 1-10 and 4-10 displayed some epileptic properties, i.e., they induced epileptic seizures (only electrographic or also behavioral) or increased hippocampal spiking. The 4-9 sequence seemed to be the common sequence responsible for these proconvulsant effects. The possible involvement of the enkephalinergic system is discussed.     

Catecholaminergic component of the action of a heptapeptide analog of ACTH4-10 on the open-field behavior of rats

Heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro (ACTH4-10 analog) at a dose of 0.015 mg/kg failed to alter open field behaviour of rats in the first test series. The peptide abolished amphetamine-induced stimulation of the exploratory and grooming behaviour. Extinction of the rats' exploratory behaviour during second test series in the open field (7 days later) was disturbed when haloperidol or apomorphine were injected before the first test series. When the peptide was administered with haloperidol or apomorphine, the extinction tended to become normal. Heptapeptide failed to change noradrenaline, dopamine or 5-hydroxytryptamine content in the rat forebrain. However, this peptide at a concentration of 10(-4) M moderately diminished tyrosine hydroxylation velocity in the rat striatal or hypothalamic synaptosomes, the effect depending on tyrosine concentration. These data suggest the involvement of catecholaminergic component into the heptapeptide action on the behaviour of rats.     

Neurochemical effects of the synthetic ACTH4-9-analog Hoe 427 (Ebiratide) in rat brain

The ACTH4-9-analog Hoe 427 systemically injected in a dose range from 0.01-10 micrograms/kg caused a fall in acetylcholine (ACh) content in different brain areas of the rat. This effect occurred 0.5 hour after a single administration and lasted up to 24 hours. The decrease in ACh content induced by Hoe 427 was more pronounced when the animals were pretreated with dexamethasone (over 7 days 1 mg/kg SC, daily). Coadministration of the choline uptake inhibitor hemicholinium-3 (HC-3) and Hoe 427 potentiated the decrease in ACh content induced by HC-3. In the same dose range Hoe 427 acutely evoked an increase of the activity of the enzyme choline acetyltransferase as well as an elevation of brain cyclic GMP content. These data indicate that Hoe 427 enhances ACh metabolism in rat brain after systemic administration.     

ACTH4-9类似物对小鼠海马突触体Ca2+水平的调节作用

本工作观察了Ｏｒｇ２７６６（ＡＣＴＨ４－９的类似物）对海马突触体内游离Ｃａ＾２＋水平及对＾４５Ｃａ＾２＋摄取的影响。采用细胞内钙离子荧光探针Ｆｕｒａ－２,通过Ｓｐｅｘ－阳离子测定系统检测突触体内［Ｃａ＾２＋］ｉ的动态变化,并用液闪光谱仪测定突触体对＾４５Ｃａ＾２＋的摄取。结果表明：较低剂量的ＯＲＧ２７６６对突触体内［Ｃａ＾２＋］ｉ的影响不明显,却显著降低突触体对＾４５Ｃａ＾２＋的摄取;高剂量的Ｏｒ     

Degradation of the ACTH(4-10) analog Semax in the presence of rat basal forebrain cell cultures and plasma membranes

Summary. Here a new approach of the elucidation of paths of proteolytic biodegradation of physiologically active peptides, based on the use of a peptide with isotopic label at all amino acid residues and the enrichment of HPLC samples with unlabeled peptide fragments in UV-detectable concentration, has been proposed. The method has been applied for the investigation of degradation dynamics of the neuroactive heptapeptide MEHFPGP (Semax) in the presence of plasma membranes, and cultures of glial and neuronal cells obtained from the rat basal forebrain. The splitting away of ME and GP, and formation of pentapeptides are the predominant processes in the presence of all tested objects, whereas the difference in patterns of resulting peptide products for glial and neuronal cells has been detected. In conclusion, the approach applied allows analyzing physiologically active peptide concentrations in biological tissues and degradation pathways of peptides in the presence of targets of their action.     

Role of chain termini in selective steroidogenic effect of ACTH/MSH(4-10) on isolated adrenocortical cells

To investigate the role of charged chain ends in the corticosteroidogenic effect of ACTH/MSH(4-10), acetyl and amide derivatives of ACTH/MSH(4-10) were synthesized and tested in isolated zona glomerulosa and zona fasciculata cells. ACTH/MSH(4-10)-NH2, Ac-ACTH/MSH(4-10) and Ac-ACTH/MSH(4-10)-NH2 (10 microM to 1 mM) stimulated the aldosterone production of zona glomerulosa cells, whereas these peptides did not stimulate the corticosterone production of zona fasciculata cells, even at 1 mM concentration. As ACTH/MSH(4-10) has been shown to have a steroidogenic effect on both types of adrenocortical cells, both charged chain termini seem to be essential for triggering of the corticosterone production of zona fasciculata cells, but for aldosterone production their presence appears not to be important.     

Acceleration of recovery from sciatic nerve damage by the ACTH(4–9) analog Org 2766: Different routes of administration

Functional recovery following a sciatic nerve crush in rats was investigated by measuring the reflex withdrawal of the hindpaw to a hot air stream. The ACTH(4–9) analog Org 2766 accelerated recovery when administered subcutaneously (two-daily injections: 10 μg/animal; minipumps: 20–40 μg/animal per 24 hr; biodegradable microspheres: 40 μg/animal per 24 hr), but oral administration (1.5–20 mg/animal daily, in the drinking water; 1.5–15 mg/animal daily, by gavage) was not effective.     

Acute sleep deprivation and circadian misalignment associated with transition onto the first night of work impairs visual selective attention

Background

Overnight operations pose a challenge because our circadian biology promotes sleepiness and dissipates wakefulness at night. Since the circadian effect on cognitive functions magnifies with increasing sleep pressure, cognitive deficits associated with night work are likely to be most acute with extended wakefulness, such as during the transition from a day shift to night shift.

Methodology/Principal Findings

To test this hypothesis we measured selective attention (with visual search), vigilance (with Psychomotor Vigilance Task [PVT]) and alertness (with a visual analog scale) in a shift work simulation protocol, which included four day shifts followed by three night shifts. There was a nocturnal decline in cognitive processes, some of which were most pronounced on the first night shift. The nighttime decrease in visual search sensitivity was most pronounced on the first night compared with subsequent nights (p = .04), and this was accompanied by a trend towards selective attention becoming ‘fast and sloppy’. The nighttime increase in attentional lapses on the PVT was significantly greater on the first night compared to subsequent nights (p<.05) indicating an impaired ability to sustain focus. The nighttime decrease in subjective alertness was also greatest on the first night compared with subsequent nights (p<.05).

Conclusions/Significance

These nocturnal deficits in attention and alertness offer some insight into why occupational errors, accidents, and injuries are pronounced during night work compared to day work. Examination of the nighttime vulnerabilities underlying the deployment of attention can be informative for the design of optimal work schedules and the implementation of effective countermeasures for performance deficits during night work.