Abstract
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.
Highlights
Autism spectrum disorders (ASDs) are characterized by a triad of symptoms that includes impaired communication, social impairments, and restricted and repetitive behaviors and interests [1]
In WT mice, we found the highest levels of oxytocin receptor (OXTR) in the olfactory bulb (OB, 0.91 ± 0.25), the anterior olfactory nucleus (AON) (0.88 ± 0.22), and in some posterior nuclei of the amygdala, the amygdalohippocampal area (AHiPM, 0.94 ± 0.16), the posteromedial cortical amygdaloid area (PMCo, 1.06 ± 0.16), and the posterior part of the basolateral amygdaloid nucleus (BLP, 0.87 ± 0.16)
ABSENCE OF MOR INDUCES SPECIFIC INCREASES OF OXTR EXPRESSION IN THE AONm, IN THE ANTERIOR AMYGDALOID NUCLEI AND IN NACCS In order to reveal possible interaction(s) between MOR and OXTR, we looked for alterations in oxytocinergic binding levels in the brains of Oprm1−/− mice
Summary
Autism spectrum disorders (ASDs) are characterized by a triad of symptoms that includes impaired communication, social impairments, and restricted and repetitive behaviors and interests [1]. The prevailing hypothesis regarding the physiopathology of ASDs identifies the area of social cognition as a primary deficit. It focuses on the impaired capabilities of affected people to attribute mental states to others (and oneself) in order to explain and predict behavior Altered affectivity is evident in autistic children [4] and, as recently proposed by Chevallier and others [5], motivation and reward processes might participate to the physiopathology of ASDs. Reward circuitry dysfunctions might lead to deficits in social seeking and maintenance, resulting in reduced social capabilities and interests, and if appearing early in life, in social learning. Excessive brain opiate activity has been proposed in the past as a neurochemical feature in autism [6] and due to their involvement in the neural circuitry of reward, μ-opioid receptors (MORs) have been investigated in relation to social reward, emotion, and social behavior [7,8,9], and represent a key target to understand the neurobiological basis of social reward dysfunction in humans and animals
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