Adolescent exposure to oxytocin, but not the selective oxytocin receptor agonist TGOT, increases social behavior and plasma oxytocin in adulthood

Suraev, Anastasia; Bowen, Michael T.; Ali, Sinan; Hicks, Callum; Ramos, Linnet; McGregor, Iain S.

doi:10.1016/j.yhbeh.2014.03.002

Cited by 32 publications

(30 citation statements)

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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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“…Similarly, in mice, a single postnatal administration of OXT at P1 facilitated alloparental care and social approach in adulthood, while administration of an OXT antagonist produced the opposite effect (62) and sub-chronic OXT treatment in juvenile rats has long lasting effects in social behavior, which is accompanied by increased plasma OXT levels (63). Interestingly, while some of these studies used male only samples (44, 63) others using both sexes found sexual dimorphism in their results, where treatment affected only males (62), only females (41, 60) or both (61). We found that a daily dose of OXT between P7 and P21 yielded effects on social behavior and increased peptide levels in brain extracts when analyzed nine days later at P30 in both sexes, which is likely due to our study of a monogenic, major gene model of ASD.…”

Section: Discussionmentioning

confidence: 99%

Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism

et al. 2015

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Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homologue of CNTNAP2, in which mutant forms cause Cortical Dysplasia and Focal Epilepsy syndrome (CDFE), displays many features parallel to the human disorder. Since CDFE has high penetrance for autism spectrum disorder (ASD) we performed an in vivo screen for drugs that treat abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment.

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“…A total volume of 5 μl of the OXT solution was administered intranasally by gently placing drops in each nostril, that were taken in when the mice reflexively inhaled (600 ng OXT/mouse). The dosage of OXT was based on data from the literature (34, 38, 39). Control mice received an equal volume of saline (Veh).…”

Section: Methodsmentioning

confidence: 99%

“…In particular, intranasal OXT administration is believed to circumvent the poor blood–brain barrier (BBB) permeability of this peptide. Even if the direct passage of intranasal OXT into the brain is still matter of debate (36, 37) acute and chronic intranasal OXT administration have been shown to exert behavioral effects in rodents (34, 38, 39). Even if it cannot be excluded that some of the behavioral effects of OXT are mediated via peripheral mechanisms, intranasal OXT administration in awake animals represents at present the most convenient and reproducible method to assess the therapeutic effects of this peptide on social behavior.…”

Section: Introductionmentioning

confidence: 99%

Region Specific Up-Regulation of Oxytocin Receptors in the Opioid Oprm1âˆ’/âˆ’ Mouse Model of Autism

et al. 2014

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Autism spectrum disorders (ASDs) are characterized by impaired communication, social impairments, and restricted and repetitive behaviors and interests. Recently, altered motivation and reward processes have been suggested to participate in the physiopathology of ASDs, and μ-opioid receptors (MORs) have been investigated in relation to social reward due to their involvement in the neural circuitry of reward. Mice lacking a functional MOR gene (Oprm1−/− mice) display abnormal social behavior and major autistic-like core symptoms, making them an animal model of autism. The oxytocin (OXT) system is a key regulator of social behavior and co-operates with the opioidergic system in the modulation of social behavior. To better understand the opioid-OXT interplay in the central nervous system, we first determined the expression of the oxytocin receptor (OXTR) in the brain of WT C57BL6/J mice by quantitative autoradiography; we then evaluated OXTR regional alterations in Oprm1−/− mice. Moreover, we tested these mice in a paradigm of social behavior, the male–female social interaction test, and analyzed the effects of acute intranasal OXT treatment on their performance. In autoradiography, Oprm1−/− mice selectively displayed increased OXTR expression in the Medial Anterior Olfactory Nucleus, the Central and Medial Amygdaloid nuclei, and the Nucleus Accumbens. Our behavioral results confirmed that Oprm1−/− male mice displayed social impairments, as indicated by reduced ultrasonic calls, and that these were rescued by a single intranasal administration of OXT. Taken together, our results provide evidence of an interaction between OXT and opioids in socially relevant brain areas and in the modulation of social behavior. Moreover, they suggest that the oxytocinergic system may act as a compensative mechanism to bypass and/or restore alterations in circuits linked to impaired social behavior.

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Adolescent exposure to oxytocin, but not the selective oxytocin receptor agonist TGOT, increases social behavior and plasma oxytocin in adulthood

Cited by 32 publications

References 50 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

Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism

Region Specific Up-Regulation of Oxytocin Receptors in the Opioid Oprm1âˆ’/âˆ’ Mouse Model of Autism

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Adolescent exposure to oxytocin, but not the selective oxytocin receptor agonist TGOT, increases social behavior and plasma oxytocin in adulthood

Cited by 32 publications

References 50 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

Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism

Region Specific Up-Regulation of Oxytocin Receptors in the Opioid Oprm1âˆ’/âˆ’ Mouse Model of Autism

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Product

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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