Pharmacologic Rescue of Impaired Cognitive Flexibility, Social Deficits, Increased Aggression, and Seizure Susceptibility in Oxytocin Receptor Null Mice: A Neurobehavioral Model of Autism

Sala, Mariaelvina; Braida, Daniela; Lentini, D; Busnelli, Marta; Bulgheroni, Elisabetta; Capurro, Valeria; Finardi, Annamaria; Donzelli, Andrea; Pattini, Linda; Rubino, Tiziana; Parolaro, Daniela; Nishimori, Katsuhiko; Parenti, Marco; Chini, Bice

doi:10.1016/j.biopsych.2010.12.022

Cited by 324 publications

(298 citation statements)

References 59 publications

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“…X. laevis oocytes do not endogenously express OTRs (31), and OTR RNA was not coexpressed into the oocytes because we injected cells with RNA only for the α4, β, and δ GABA A R subunits. This finding is consistent with recent studies demonstrating that a range of OT functional effects rely on receptors other than the OTR (32)(33)(34)(35)(36). OT has, however, been found to alter the expression and function of GABA A Rs, albeit via an OTRmediated mechanism (37)(38)(39).…”

Section: Discussionsupporting

confidence: 92%

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Bowen

Peters

Absalom

et al. 2015

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

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Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at δ subunit-containing GABA A receptors (δ-GABA A Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at δ-GABA A Rs and that this effect does not involve the oxytocin receptor. Specifically, oxytocin (1 μg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats. Using twoelectrode voltage-clamp electrophysiology in Xenopus oocytes, oxytocin was found to completely block ethanol-enhanced activity at α4β1δ and α4β3δ recombinant GABA A Rs. Conversely, ethanol had no effect when applied to α4β1 or α4β3 cells, demonstrating the critical presence of the δ subunit in this effect. Oxytocin had no effect on the motor impairment or in vitro effects induced by the δ-selective GABA A R agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, which binds at a different site on δ-GABA A Rs than ethanol. Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABA A Rs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABA A Rs. Finally, our in vitro constructs did not express any oxytocin receptors, meaning that the observed interactions occur directly at δ-GABA A Rs. The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.A receptors (δ-GABA A Rs) play a major role in regulating tonic inhibition in the central nervous system (CNS) (1). The δ-GABA A Rs also represent one of the major targets of ethanol in the CNS, particularly at relatively low ethanol concentrations, and mediate some of the rewarding and ataxic effects of ethanol (2-8). For instance, a genetic polymorphism that exaggerates the actions of ethanol at δ-GABA A Rs also potentiates ethanolinduced motor impairment (2). Further, knockdown of δ subunit expression in the medial shell of the nucleus accumbens reduces alcohol intake in rats (6). Finally, overstimulation and subsequent internalization of α4βδ extrasynaptic GABA A Rs after persistent stimulation by ethanol seem to underlie the development of rapid tolerance to the ataxic effects of ethanol (4).The neuropeptide oxytocin (OT) is well-known for its regulatory role in mammalian sociability and various other central and peripheral physiological processes (9). Early preclinical studies suggested that OT can prevent the development of tolerance to the sedative and ataxic effects of ethanol in rodents (10) and also modulate the severity of ethanol withdrawal (11). More recent studies show that OT reduces alcohol intake in rats (12) and reduces the severity of a...

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Section: Discussionsupporting

confidence: 92%

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Bowen

Peters

Absalom

et al. 2015

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

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“…The properties of the USVs were similar in both groups; the frequency was approximately 70 kHz and the mean duration was approximately 60 ms. These results are consistent with previous observations in Oxt -/-and Oxtr -/-mice (Nishimori et al, 1996;Takayanagi et al, 2005;Sala et al, 2011).…”

Section: Cd38 Knockout Micesupporting

confidence: 94%

“…Similarly, Oxtr -/-mice are viable and have no obvious defects in fertility or sexual behavior. In addition, dams exhibit normal parturition, but display defects in lactation and maternal nurturing (Takayanagi et al, 2005;Sala et al, 2011). These results indicate that, in the OXT/CD38/OXTR signaling pathway, OXT and OXTR are not essential for normal parturition but are required for milk ejection, while CD38 is not critically involved in reproduction.…”

Section: Cd38 Knockout Micementioning

confidence: 94%

“…Subcutaneous administration of low doses of OXT also facilitates social recognition (Popik et al, 1992). Two mouse models with either OXT or OXT receptor (OXTR) gene knockouts (Oxt / or Oxtr / , respectively) show signs of profound social amnesia (Nishimori et al, 1996;Ferguson et al, 2000;Takayanagi et al, 2005;Crawley et al, 2007;Macbeth et al, 2010;Sala et al, 2011), which was rescued in the OXT knockout mice by the administration of OXT. These observations suggest that OXT plays an important role in social behavior via the stimulation of the OXTR during brain development and throughout the juvenile and adult life-stages (Ahern and Young, 2009;Carter et al, 2009;Insel, 2010).…”

Section: Introductionmentioning

confidence: 99%

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CD38 and its role in oxytocin secretion and social behavior

Higashida

Yokoyama

Kikuchi

et al. 2012

Hormones and Behavior

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Here, we review the functional roles of cyclic ADP-ribose and CD38, a transmembrane protein with ADP-ribosyl cyclase activity, in mouse social behavior via the regulation of oxytocin (OXT) release, an essential component of social cognition.Herein we describe data detailing the molecular mechanism of CD38-dependent OXT secretion in CD38 knockout mice. We also review studies that used OXT, OXT receptor (OXTR), or CD38 knockout mice. Additionally, we compare the behavioral impairments that occur in these knockout mice in relation to the OXT system and CD38.This review also examines autism spectrum disorder (ASD), which is characterized by social and communication impairments, in relation to defects in the OXT system. Two single nucleotide polymorphisms (SNPs) in the human CD38 gene are possible risk factors for ASD via inhibition of OXT function. Further analysis of CD38 in relation to the OXT system may provide a better understanding of the neuroendocrinological roles of OXT and CD38 in the hypothalamus and of the pathophysiology of ASD.3

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“…We approximated the dose of the drug based on prior studies [57], and in our experiments at least one-tenth of the effective dose did not modify the effects of ECT at all. Still, the involvement of vasopressin receptors cannot be discounted, particularly considering that vasopressin has been implicated in regulating social behaviors and mechanisms of autism [58,59]. A more definitive answer could be obtained from the examination of autism in oxytocin and/or oxytocin knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

et al. 2015

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Autism is a developmental disorder characterized by impairments in social and communication abilities, as well as by restricted and repetitive behaviors. Incidence of autism is higher than earlier estimates, and treatments have limited efficacy and are costly. Limited clinical and experimental evidence suggest that patients with autism may benefit from electroconvulsive therapy (ECT). We examined the therapeutic potential of ECT in BTBR T+ tf/j mice, which represent a validated model of autism. A series of 13 electroconvulsive shocks (ECS) delivered twice a day over 7 days reversed core autism-like behavioral abnormalities-impaired sociability, social novelty, and repetitive behavior-when the animals were tested 24 h after the last ECS. The effect lasted up to 2 weeks after ECT. Neither single ECS nor a series of 6 ECS modified animals' behavior. Chronic infusion into the lateral brain ventricle of a preferential oxytocin receptor blocker (2S)-2-Amino--(methylsulfonyl)butanamide hydrochloride abolished ECTinduced improvement of sociability and mitigated improvement of social novelty but did not affect ECT-induced reversal of repetitive behavior. These proof-of-principle experiments suggest that ECT may, indeed, be useful in the treatment of autism, and that its therapeutic effects may be mediated, in part, by central oxytocin signaling.

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Pharmacologic Rescue of Impaired Cognitive Flexibility, Social Deficits, Increased Aggression, and Seizure Susceptibility in Oxytocin Receptor Null Mice: A Neurobehavioral Model of Autism

Cited by 324 publications

References 59 publications

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

CD38 and its role in oxytocin secretion and social behavior

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

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Pharmacologic Rescue of Impaired Cognitive Flexibility, Social Deficits, Increased Aggression, and Seizure Susceptibility in Oxytocin Receptor Null Mice: A Neurobehavioral Model of Autism

Cited by 324 publications

References 59 publications

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

CD38 and its role in oxytocin secretion and social behavior

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

Contact Info

Product

Resources

About

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats