Brief report: A double-blind study of naltrexone in infantile autism

Leboyer, Marion; Bouvard, Manuel; Launay, Jean‐Marie; Tabuteau, F; Waller, D.; Dugas, Michel J.; Kerdelhué, B.; Lensing, Patrick; Panksepp, Jaak

doi:10.1007/bf01058158

Cited by 119 publications

(46 citation statements)

References 22 publications

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“…Thus, it has been hypothesized that abnormalities in AVP and OT may play an important role in disorders like autism, in which disturbances in social behavior are the main characteristics (Insel et al, 1999). Indeed abnormal basal concentrations of AVP and OT have been found in autistic children: basal AVP concentrations were found to be increased (Leboyer et al, 1992) and OT concentrations were found to be decreased (Modahl et al, 1998). Thus, the elevated cortisol response to psychosocial stress might be explained by increased stimulation by AVP and decreased inhibition by OT.…”

Section: Discussionmentioning

confidence: 99%

Differentiation between Autism and Multiple Complex Developmental Disorder in Response to Psychosocial Stress

Jansen

Wied

Gaag

et al. 2002

Neuropsychopharmacol

100

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Multiple Complex Developmental Disorder (MCDD) represents a distinct group within the autistic spectrum based on symptomatology. Unlike autistic children, part of MCDD children develop schizophrenia in adult life. Despite the differences, patients of both disorders are mainly characterized by abnormal reactions to their social environment. At the biological level, we showed in a previous study that MCDD children have a reduced cortisol response to psychosocial stress. Given the fact that autistic children clinically show more social impairments, it was hypothesized that they may have even further decreased cortisol responses to psychosocial stress than MCDD patients. Therefore, 10 autistic children were compared to 10 MCDD children and 12 healthy control children in their response to a psychosocial stressor, consisting of a public speaking task. In order to test whether any impairments in the biological stress response are specific for psychosocial stress, the autistic children were compared with 11 MCDD children and 15 control children in their response to a physical stressor, consisting of 10 min of bicycle exercise. Heart rate and salivary cortisol levels were used as indicators of response to the stress tests. Autistic children showed a relatively elevated cortisol response to psychosocial stress, in contrast to MCDD children who showed a reduced cortisol response. No differences in heart rate or cortisol responses to the physical stress test were found. The specific difference between autistic and MCDD children in their cortisol response to psychosocial stress indicates that the disturbed reactions to the social environment observed in these disorders may have different biological backgrounds.

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Section: Discussionmentioning

confidence: 99%

Differentiation between Autism and Multiple Complex Developmental Disorder in Response to Psychosocial Stress

Jansen

Wied

Gaag

et al. 2002

Neuropsychopharmacol

100

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“…Autism is a childhood disorder characterized by disruption in socially relevant behaviors [57, 58]with a strong aggression component [59]. OT levels have been shown to be strongly reduced [60]and VP levels have been shown to be abnormal in autistic children [61]. A parallel reduction in OT in the brain can occur [62].…”

Section: Discussionmentioning

confidence: 99%

Vasopressin Stimulates Ventromedial Hypothalamic Neurons via Oxytocin Receptors in Oxytocin Gene Knockout Male and Female Mice

et al. 2004

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A wealth of neuropharmacological data demonstrates that oxytocin (OT) actions in the mammalian forebrain support a wide variety of affiliative behaviors and repress aggressive behaviors. Based on that literature, it was expected that reproductive and affiliative behaviors would be vastly decreased and aggression markedly increased in OT gene knockout (OTKO) mice. The initial publications reporting the behaviors of these mice did not include such phenotypes. Here, we compared single-unit activities recorded from the ventromedial hypothalamus in tissue slices of male and female OTKO mice and their wild-type littermate to test two hypotheses about OT functional genomics. First, we proposed that in OTKO mice, a very similar 9-amino-acid neuropeptide, arginine vasopressin (a likely gene duplication product), can ‘cross over’ and compensate for the lack of OT. This hypothesis was confirmed in both males and females. Further, we proposed that because of the lifelong absence of OT in OTKO, OT receptors would be more sensitive to OT in the knockout animals. We tested this idea in males and found that it was correct. Thus, an answer to the ‘OTKO paradox’ is put forth, with implications for OT-sensitive behaviors in a variety of species.

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“…The supralinear effects of OTNAL may be due to simultaneous engagement of feedforward endogenous OT release from neurons with OT receptors (46), as well as the removal of opioid-mediated inhibition of OT release in OT neurons (27), resulting in overall higher endogenous OT levels that reach a threshold needed for social functions. Observational studies in patients with autism have shown that administration of an opioid antagonist could decrease self-injurious behavior, stereotypies, hyperactivity, and withdrawal, although increasing verbal production, social communication, proximity seeking, and eye contact (47)(48)(49)(50). However, in the past decade, there has been a striking reduction in research using opioid antagonists as a means to ameliorate social deficits, whereas there has been a marked increase in studies testing the benefits of OT on social attention, although with inconclusive results.…”

Section: Discussionmentioning

confidence: 99%

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

Monte

Piva

Anderson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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To provide new preclinical evidence toward improving the efficacy of oxytocin (OT) in treating social dysfunction, we tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions in monkeys. OT coadministered with a μ-opioid receptor antagonist, naloxone, invoked a supralinear enhancement of prolonged and selective social attention, producing a stronger effect than the summed effects of each administered separately. These effects were consistently observed when averaging over entire sessions, as well as specifically following events of particular social importance, including mutual eye contact and mutual reward receipt. Furthermore, attention to various facial regions was differentially modulated depending on social context. Using the Allen Institute's transcriptional atlas, we further established the colocalization of μ-opioid and κ-opioid receptor genes and OT genes at the OT-releasing sites in the human brain. These data across monkeys and humans support a regulatory relationship between the OT and opioid systems and suggest that administering OT under opioid antagonism may boost the therapeutic efficacy of OT for enhancing social cognition.T he efficacy of oxytocin (OT) in improving social abilities is under debate, largely due to frequently observed weak effect sizes and problems with replicability (1-3). Clinical trials of OT in autistic patients are ongoing, yet several studies have produced inconclusive results (4-8), demanding improvements to the efficacy and reliability of OT-based therapeutics. One strategy is to take advantage of existing physiological pathways in the brain that regulate OT activity to combinatorially enhance the oxytocinergic effects on social functions. In this regard, a promising candidate is the opioid system.In addition to the evolutionarily conserved OT system (9), the opioid system has been implicated in regulating social behavior. Excessive opioid activity in the brain has been discussed with respect to the development of early childhood autism (10). Abnormalities in central opioid levels have been observed in some individuals with autism, and clinical trials with predominantly μ-opioid blockers, such as naltrexone or naloxone (NAL), have yielded promising results in ameliorating both social and nonsocial deficits (11). Specifically, μ-opioid receptors have been studied in relation to reward, emotion, and behavior in the social domain (12) and are strongly expressed in reward-related regions of the primate brain (13). In rhesus macaques, carrying the G allele of the μ-opioid receptor gene OPRM1, compared with homozygous C alleles, is associated with stronger maternal attachment in infants (14) and more effective prevention of infant separation in mothers (15). Additionally, opioid agonists, such as morphine, decrease physical contact between social partners, whereas NAL administration increases solicitation for social contact, such as grooming and proximity (16)(17)(18)(19).The physiological relationship between the opi...

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Brief report: A double-blind study of naltrexone in infantile autism

Cited by 119 publications

References 22 publications

Differentiation between Autism and Multiple Complex Developmental Disorder in Response to Psychosocial Stress

Differentiation between Autism and Multiple Complex Developmental Disorder in Response to Psychosocial Stress

Vasopressin Stimulates Ventromedial Hypothalamic Neurons via Oxytocin Receptors in Oxytocin Gene Knockout Male and Female Mice

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

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