The use of adrenocorticotrophic hormone (4-9) analog ORG 2766 in autistic children: effects on the organization of behavior.

In a double-blind placebo-controlled crossover trial, 14 autistic children were treated with the neuropeptide ORG 2766, a synthetic analog of adrenocorticotrophic hormone (ACTH) (4-9). ORG 2766 treatment (20 mg per day during 4 weeks) was associated with an increased amount and an improved quality of the social interaction of the autistic children with a familiar experimenter. These changes in interaction were clinically relevant. Following treatment with ORG 2766 gaze and smile behaviors of child and experimenter showed stronger temporal contingencies. Further, after ORG 2766, stereotypies were temporally disconnected from verbal initiatives. The data supported the notion of a stimulating effect of ORG 2766 on social interaction. The implications of these findings for the endogenous opioid theory of autism are discussed.     

Social and exploratory behaviour in the rat after septal administration of ORG 2766 and ACTH4-10

The time spent in active social interaction by pairs of male rats in a dimly-lit, familiar test arena, was decreased significantly after intraseptal injection of ACTH4-10 (250-500 ng). In contrast, the time spent in active social interaction was increased significantly after intraseptal injection of the tri-substituted ACTH4-9 analogue ORG 2766 (250-500 pg). Neither ACTH4-10 (250 ng) nor ORG 2766 (250 pg) affected exploration or locomotor activity measured in a holeboard, after intraseptal injection. Intraseptally administered ACTH4-10 (250 ng) increased aggression measured in a colony intruder model, but ORG 2766 (250 pg) was without effect.     

Treatment of diabetic polyneuropathy with the neurotrophic peptide ORG 2766

The efficacy of the neurotrophic peptide ORG 2766 in diabetic patients with polyneuropathy was evaluated in a double-blind, placebo-controlled, multicentre trial. One hundred and twenty four patients were randomised in five groups to receive 0.1, 0.4, 2 or 5 mg ORG 2766 or placebo, once daily, administered subcutaneously 52 weeks. Thermal discrimination thresholds (TDT) and vibration perception thresholds (VPT), motor and sensory nerve conduction velocity, Hoffmann reflex, heart rate variation during deep breathing and heart rate response after standing up, neurological examination score and neuropathic symptom score were determined at baseline and after 17, 34 and 52 weeks of treatment. Of the nerve function indices studied, at week 52 the TDT_warmth of the hand in the ORG 2766 0.1, 0.4 and 5 mg groups and the TDT_cold of the foot in the ORG 2766 0.1 and 0.4 mg groups significantly improved compared with placebo. Further significant improvement as compared with placebo was observed in the paraesthesia score at week 34 and week 52 in the ORG 2766 2 mg group. Only at week 34 had both the heartbeat variation during deep breathing and the VPT of the foot in the ORG 2766 0.1 mg group improved significantly, compared with placebo. No further statistically significant differences were observed at time for the other measures. No adverse reactions were observed. The only recorded drug-induced side effect was pain at the injection site. Taking all measures of efficacy into account, the statistically significant results observed did not show consistency within each measure. Therefore, it is concluded that ORG 2766, in contrast to earlier reports, is not effective in treating diabetic polyneuropathy.     

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. II. Facilitation by the ACTH-(4-9) analog ORG 2766

Functional recovery from motor hypoactivity of rats with 6-OHDA lesions in the nucleus accumbens is accelerated by intra-accumbal or subcutaneous treatment with the ACTH-(4-9) analog ORG 2766. The spontaneous recovery period of 3 weeks is shortened to 7 days by daily treatment with this peptide during the first 6 days after the lesion. The 6-OHDA lesion induced a decrease of about 30-40% in the levels of dopamine, HVA and DOPAC as well as in the uptake of [3H]dopamine in nucleus accumbens tissue in vitro. Treatment with ORG 2766 during the first 6 days following the lesion did not affect the lesion-induced changes in these biochemical parameters. Binding studies with [3H]haloperidol in nucleus accumbens tissue of placebo or ORG 2766-treated sham-lesioned rats revealed a linear Scatchard plot 7 days after the sham lesion. In tissue of placebo-treated 6-OHDA lesioned animals a similar linear Scatchard plot was found but in tissue of ORG 2766-treated 6-OHDA-lesioned rats the Scatchard plot was curvilinear in shape indicating two types of binding sites. In the 6-OHDA-lesioned rats treated with ORG 2766 the behavioral response upon apomorphine challenge was enhanced suggesting the existence of functional supersensitivity of the DA system. Similar changes in Scatchard plots and apomorphine-induced behavioral changes have been previously reported after spontaneous recovery. The present study indicates that ORG 2766 accelerates the process of functional recovery from impaired motor behavior of rats with 6-OHDA lesions in the nucleus accumbens, which may be due to development of denervation supersensitivity.     

The ACTH-(4–9) analogue ORG 2766 facilitates denervation supersensitivity after a unilateral 6-OHDA lesion of the corpus striatum in rats

Direct bilateral 6-OHDA lesioning of the nucleus accumbens causes a temporary reduction in motility, followed by a spontaneous recovery in 3-4 weeks. The ACTH-(4-9) analogue ORG 2766 shortens this period to 1 week. The functional and the peptide-induced facilitation of recovery are accompanied by enhanced motility upon administration of the dopamine agonist apomorphine which may be related to denervation supersensitivity. The present experiments were performed to investigate the interaction between ORG 2766 and denervation supersensitivity in another dopaminergic terminal area i.e. the corpus striatum. After a unilateral 6-OHDA lesion of the right corpus striatum, contralateral rotation was observed upon administration of a high dose of apomorphine 2, 3 and 4 weeks after the lesion, indicating supersensitivity of postsynaptic dopaminergic receptor systems. Contralateral rotation upon administration of this dose of apomorphine was observed in ORG 2766 treated animals, already at 1 week after the lesion. Peptide treatment resulted in an enhanced sensitivity for apomorphine, since contralateral rotation was observed in peptide but not in placebo treated, 6-OHDA lesioned animals after a low dose of apomorphine. In conclusion: treatment with ORG 2766 facilitates the development of denervation supersensitivity and enhances sensitivity for apomorphine probably through an increased affinity of dopaminergic receptors for dopamine agonists.     

Spatial learning and the hippocampal corticosterone receptor system of old rats: effect of the ACTH4–9 analogue ORG 2766

Old (26 months) and young (6 months) male Wistar rats were treated chronically for 2 weeks with ORG 2766 or with vehicle, delivered via subcutaneously implanted minipumps (0.5 μg peptide/0.5 μl/h). Learning of a spatial task was not impaired in the old animals, except for one measure, i.e. the latency to find the goal ☐. In neither age group did ORG 2766 influence behavioral performance. The number of corticosterone receptor sites was decreased in the hippocampus of senescent rats, but restored to the level observed in young rats following ORG 2766 treatment. It is concluded that the number of hippocampal corticosterone receptor sites is a sensitive index of brain aging and effectiveness of ORG 2766.     

The ACTH4-9 analog ORG 2766 'normalizes' the changes in motor activities of rats elicited by housing and test conditions

Motor activities of rats were decreased by short-term (7 days) social isolation as well as by intense light test conditions. The ACTH4-9 analog ORG 2766, s.c. administered 50 min before testing, dose-dependently decreased the high motor activities of group-housed rats tested under low light conditions and increased the low motor activities of short-term isolated rats tested under intense light conditions (ED50: 0.01-0.03 microgram/kg). Structure-activity studies suggest that the essential structure for these effects may be located in the C-terminal tripeptide Phe-D-Lys-Phe. Treatment with ACTH4-10 (100 micrograms/kg) tended to enhance some of the effects of the environmental conditions. Pretreatment of rats with the opioid antagonist naltrexone (450 micrograms/kg, s.c.) completely blocked the 'normalizing' effects of ORG 2766, implicating endogenous opioids in this action of ORG 2766. Since social behaviors of rats are similarly affected by ORG 2766 as motor activities, it is suggested that this peptide affects the integration of sensoric stimuli rather than the specific motor output systems of these behaviors.     

Protection against cisplatin induced neurotoxicity by ORG 2766: histological and electrophysiological evidence

Prolonged administration of the anti-tumor agent cisplatin may cause a neuropathy in patients. In an animal model, too, neurotoxicity, as evidenced by a decrease in H-related sensory nerve conduction velocity (SNCV), can be induced by repetitive injections of cisplatin. In an attempt to further the insight into the effects of cisplatin on the peripheral nervous system a combined electrophysiological and histomorphological investigation was performed on 2 groups of 6 rats, treated with cisplatin for 7.5 weeks, and a control group (n = 6). Concomitant administration of ORG 2766, an ACTH(4–9) analog, was previously shown to prevent cisplatin neurotoxicity in this model and more recently in patients as well. One group of rats was therefore co-treated with this peptide during the complete treatment period. A marked decrease in SCNV was observed in cisplatin/saline treated rats, but not in cisplatin/ORG 2766 treated rats. Though no statistically significant difference was seen in the total number of myelinated fibers in the sural nerves of cisplatin treated rats, a decrease in the proportion of thick myelinated fibers was present in the cisplatin/saline treated rats. This shift in fiber distribution was absent in ORG 2766 co-treated animals. Mean internodal distances and g-ratios were not affected, and signs of axonal degeneration, or de- or remyelination were not observed.     

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. III. Further analysis of the facilitating effect of the ACTH-(4-9) analog ORG 2766

The functional recovery from impaired motor activity caused by 6-OHDA lesions in the nucleus accumbens is accelerated by the ACTH-related peptides ACTH-(4-10), alpha-MSH (ac-Ser1-ACTH-(1-13)NH2), ACTH-(7-10) and the ACTH-(4-9) analog ORG 2766. The peptides ACTH-(4-7) and Phe-D-Lys-Phe were not effective in this respect. This indicates that this effect of ACTH-derived peptides is located in the 7-10 part of the molecule whereas for the effect of ORG 2766 a bigger part of the molecule may be required. ORG 2766 was effective after intra-accumbal, subcutaneous and oral administration. The differences in potencies between the 3 routes of administration (ED50 0.76 ng/kg, 28.5 ng/kg and 80.6 micrograms/kg, respectively) suggest that the peptide exerts its effect by facilitating recovery processes at the lesion site. Studies with ORG 2766 showed that treatment during the first days following the induction of the lesion is essential for the facilitating action of the peptide on spontaneous recovery from brain damage.     

Opioid systems in the amygdala can serve as substrate for the behavioral effects of the ACTH-(4-9) analog ORG 2766

Rats housed individually for 7 days showed a marked decrease in motor activity when tested under intense light conditions in a novel environment as compared to group-housed rats tested under low light conditions. The ACTH analogue ORG 2766 administered into the amygdala decreased the motor activity of group-housed rats tested under low light conditions and increased the motor activity of 7-days isolated rats tested under intense light conditions (ED50: 1-10 pg). Injection of the peptide into the nucleus accumbens was not effective, suggesting that ORG 2766 affects the integration of sensoric stimuli rather than the specific motor output systems. Pretreatment of the rats with the opiate antagonist naltrexone in the amygdala completely blocked the effect of ORG 2766. A similar blockade of the ORG 2766-induced effect could be induced by pretreatment with endorphin antibody suggesting that the "normalizing" activity of ORG 2766 on environmentally induced behavioral changes is mediated by the release of endogenous opioid peptides.     

Early postnatal treatment with ACTH4-9 analog ORG 2766 improves adult spatial learning but does not affect behavioural stress reactivity

Studies on adult animals and humans have shown that the ACTH4-9 analog ORG 2766 influences cognitive performance and possibly has neurotrophic effects. For this reason we studied the effect of ORG 2766 applied in early postnatal life when brain structures and neuronal pathways are still developing. Our aim was to see whether such treatment during development would result in permanent changes in adult behavioural performance. Pups received subcutaneous injections of 1 microg/g bodyweight ACTH4-9 analog ORG 2766 on day 1, 3 and 5 after birth. Control animals in the same nest received saline injections. When the animals had reached an adult age of 3 months they were subjected to a series of tests to measure their behavioural performance. In the first experiment, behavioural stress responses and anxiety were measured by subjecting the rats to the following tests: open field, defensive burying, elevated plus maze, and conditioned fear test. In a second experiment, adult cognitive function was measured in the Morris water-maze, a hippocampus-related spatial learning test, and in the active avoidance test, a more amygdala-related nonspatial test. The results showed that animals treated with ORG 2766 during early postnatal life learned faster in the spatial Morris water-maze. The treatment had a positive effect on performance during the acquisition phase of the learning task, while memory retrieval was not affected. Learning in the nonspatial active avoidance task did not change due to the postnatal ACTH4-9 treatment. In addition, there were no differences in the open field test, the defensive burying test, elevated plus maze and the conditioned fear test. The latter supports the conclusion that the differences in water-maze performance was due to a difference in learning speed, rather than a difference in anxiety or behavioural stress reactivity. Analysis of [3H]CORT binding capacity measured after the learning tests revealed no differences in the hippocampal MR and GR concentration between non-treated and treated animals.     

A new approach for the evaluation of recovery after peripheral nerve damage

The major caudal nerves of the rat provide an excellent model for longitudinal evaluation of nerve repair following a crush lesion. The surgical procedure and the method for testing sensory recovery are described in detail. Using this technique a clear, positive effect of ORG.2766 (an ACTH (4-9) analog) on the regeneration of sensory nerves could be shown. Results support the suggestion that ORG.2766 enhances the initial sprouting response, rather than exerting an effect on the growth rate of newly developed sprouts.     

Chronic administration of ORG 2766 for 6 months produces a subtle impairment in strategic learning by rats

Rats were administered saline or 10 μg of the ACTH_4–9 analog ORG 2766 on alternate days for 160 days (i.e. 80 injections total). Behavioral assessments began 1 week later. Locomotor competence was assessed by examining the number of slips and falls made by the animals on a rotating rod. The rats were also trained on a position task and 10 subsequent position reversals in a ‘T’ shaped water maze. Exposure to ORG 2766 failed to affect either locomotor competence or the overall number of errors committed while learning the original position habit and 10 reversals. However, the response accuracy of the ORG 2766-treated animals on trial 2 of the reversals was equivalent to that expected by chance (58% correct choices), whereas saline-treated animals effectively altered their behavior after experiencing nonreinforcement on the initial trial of a reversal (77% correct choices). This result is consistent with other observations revealing that ORG 2766 can influence attention and, therefore, some cognitive functions.     

ORG 2766 fails to improve visual functions in rats with occipital lesions.

Adult rats were trained on a white versus black card discrimination in a circular water tank. Three independent variables were manipulated: lesion (sham, lateral occipital, medial occipital), dose of ORG 2766 administered (0 or 25 micrograms in saline on alternate days for 18 days), and time of administration (during the post-surgical recovery interval or during post-operative testing). Both visual cortical lesions produced a prominent retention deficit and defective pattern vision. Neither post-surgical nor concurrent administration of ORG 2766 improved visual functions. These results, along with a growing body of evidence, challenge the generality of the positive influences of ORG 2766 upon behavioral recovery observed in animals with limbic lesions.     

Chronic and intra-amygdala administrations of the ACTH(4–9) analog ORG 2766 modulate behavioral changes after manipulation of NMDA-receptor activity

Microinjection of N-methyl- -aspartic acid (NMDA, 300 ng/3 μl) into the left lateral ventricle causes a substantial increase in locomotor activity which can be significantly reduced by a chronic pretreatment with the ACTH(4–9) analogue ORG 2766 (1 μg/0.5 ml saline, subcutaneous (s.c.) every day for 7 days, last injection 24 h before the NMDA-injection). A single dose of ORG 2766 (1 ng/1 μl) injected into the left central amygdaloid nucleus 30 min before the NMDA-injection was equally effective in reducing the increase in locomotion. Furthermore it counteracted the predominance of contralateral turning induced by the NMDA-injection. The data give support for the idea that ORG 2766 excerts its effects on behavior and neural recovery by modulating NMDA receptor activity in the brain.     

RCT examining the effect of treatment intensity for a psychosocial treatment for high-functioning children with ASD

This randomized controlled trial evaluated the effect of treatment intensity (high intensity vs. lower intensity) on the feasibility and efficacy of a comprehensive psychosocial treatment for 47 high-functioning children, ages 7–12 years with ASD (HFASD). All participants received the comprehensive 5-week summer treatment (summerMAX), with half receiving the previously validated high-intensity (HI) program (2:1 child-to-staff ratio) and half receiving a lower intensity (LI) version of the same program (4:1 child-to-staff ratio). Results of the primary analyses indicated significant improvements on non-literal language and emotion recognition (decoding) child testing and parent ratings of targeted and broad social skills, ASD-related symptoms, withdrawal, and behavioral symptoms for the overall group (HI and LI combined) and no significant difference between the conditions (HI vs. LI). Secondary staff clinician ratings corroborated parent ratings. No significant cross-condition differences were observed in fidelity of implementation or in parent, child, or staff clinician satisfaction ratings indicating no reduction in feasibility for the LI group. Overall, results suggested that similar positive outcomes can be achieved when the summerMAX program is administered at a lower intensity level.     

A prospective, open-label trial of galantamine in autistic disorder

OBJECTIVE: Post-mortem studies have reported abnormalities of the cholinergic system in autism. The purpose of this study was to assess the use of galantamine, an acetylcholinesterase inhibitor and nicotinic receptor modulator, in the treatment of interfering behaviors in children with autism. METHODS: Thirteen medication-free children with autism (mean age, 8.8 +/- 3.5 years) participated in a 12-week, open-label trial of galantamine. Patients were rated monthly by parents on the Aberrant Behavior Checklist (ABC) and the Conners' Parent Rating Scale-Revised, and by a physician using the Children's Psychiatric Rating Scale and the Clinical Global Impressions scale. RESULTS: Patients showed a significant reduction in parent-rated irritability and social withdrawal on the ABC as well as significant improvements in emotional lability and inattention on the Conners' Parent Rating Scale--Revised. Similarly, clinician ratings showed reductions in the anger subscale of the Children's Psychiatric Rating Scale. Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. Overall, galantamine was well-tolerated, with no significant adverse effects apart from headaches in one patient. CONCLUSION: In this open trial, galantamine was well-tolerated and appeared to be beneficial for the treatment of interfering behaviors in children with autism, particularly aggression, behavioral dyscontrol, and inattention. Further controlled trials are warranted.     

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. IV. Delay by intra-accumbal treatment with ORG 2766- or alpha-MSH antiserum

Rats with 6-OHDA lesions in the nucleus accumbens which were treated intra-accumbally with control serum during the first week following the lesion showed a similar level of motor activity 3 weeks after the lesion as sham-lesioned rats treated with control serum. In 6-OHDA-lesioned rats that were identically treated with antiserum against alpha-MSH or the ACTH-(4-9) analog ORG 2766 motor activity was decreased 3 weeks after the lesion. Intra-accumbal treatment with the antisera did not affect motor activity of sham-lesioned rats. The increased motor activity after apomorphine injection into the nucleus accumbens of control serum-treated 6-OHDA-lesioned rats was not observed in 6-OHDA-lesioned rats treated with the antisera. Furthermore, [3H]haloperidol binding studies showed that the changes in the DA receptor systems in the nucleus accumbens of 6-OHDA-lesioned rats treated with control serum, which may reflect denervation supersensitivity, were not observed in 6-OHDA-lesioned rats treated with the antisera. The present data indicate that the functional recovery and the concurrent development of supersensitive DA receptor systems in the nucleus accumbens of 6-OHDA-lesioned rats are delayed by intra-accumbal treatment with ORG 2766 or alpha-MSH antiserum. This suggests that endogenous ACTH/MSH-like factors may be mediating the recovery processes.     

Cerebral 2-deoxyglucose accumulation in mice following chronic treatment with an ACTH4–9 analog, ORG 2766

Mice were treated with [MET(O2)4, D-Lys8,Phe9]ACTH4-9 (ORG 2766, 100 micrograms/kg per day SC) for 10 days. On the tenth day mice were injected with [3H]2-deoxyglucose and its cerebral accumulation determined in 17 brain areas. The combined results of four experiments indicated a significant decrease of the 2-deoxyglucose accumulation in the septum. Changes observed in other brain areas were not statistically significant in the combined analysis of all four experiments. This selective change in the septum is consistent with selective uptake of ORG 2766 in this region, and with the lack of behavioral activity of ACTH in septal lesioned animals. It also suggests that the behavioral activity of this peptide, generally considered to be on arousal, vigilance, and/or selective attention, may be mediated through the septum, a limbic system structure.     

Does brief,clinically based,intensive multimodal behavior therapy enhance the effects of methylphenidate in children with ADHD?

OBJECTIVE: The additional value of a short-term, clinically based, intensive multimodal behavior therapy to optimally titrated methylphenidate in children with attention-deficit hyperactivity disorder (ADHD) was investigated. METHOD: Fifty children with ADHD (ages 8-12) were randomized to treatment of methylphenidate or treatment with methylphenidate combined with 10 weeks of multimodal behavior therapy. The multimodal behavior therapy consisted of a child and parent behavioral therapy and a teacher behavioral training. Assessments included parent, teacher and child ratings of ADHD symptoms, oppositional and conduct behavior, social skills, parenting stress, anxiety and self-worth. RESULTS: Both treatment conditions yielded significant improvements on all outcome domains. No significant differences were found between both treatments. CONCLUSIONS: No evidence was found for the additive effect of multimodal behavior therapy next to optimally titrated methylphenidate. CLINICAL IMPLICATIONS: This study does not support the expectation that optimally dosed stimulant treated children with ADHD should routinely receive psychosocial treatment to further reduce ADHD- and related symptoms.