Region Specific Up-Regulation of Oxytocin Receptors in the Opioid Oprm1−/− Mouse Model of Autism

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.

The oxytocin analogue carbetocin prevents priming-induced reinstatement of morphine-seeking: Involvement of dopaminergic, noradrenergic and MOPr systems

“…The effect of CBT on striatal dopamine and noradrenaline turnover was assessed by two-way ANOVA with factors 'treatment' (saline/CBT) and 'experiment' (priming-/stress-induced reinstatement). For analysis of OTR autoradiographic binding, unpaired Student's t-test in each individual region was used, as previously described (Gigliucci et al, 2014). ANOVAs were followed by a Holm-Sidak post-hoc test when significance was reached (p< 0.05).…”

“…The neurochemical mechanism underlying the behavioural effect of CBT was also investigated by comparing the involvement of the striatal noradrenergic and dopaminergic systems in CBT reversal of priming-and stress-induced reinstatement of opioid CPP a. In addition, given the evidence suggesting the presence of OTR-MOPr interactions in the brain (Becker et al, 2014;Gigliucci et al, 2014), which might also be involved in the modulation of opioid addiction and relapse, we further explored these receptor interactions by carrying out OTR autoradiographic binding in brains of MOPr knockout mice.…”

Assembling the Puzzle: Pathways of Oxytocin Signaling in the Brain

“…Nevertheless, in preclinical animal models characterized by autistic-like symptoms, OT administration has been reported to rescue social deficits when given just after birth or in the first postnatal days (74)(75)(76)(77)(78) or in young adults (79)(80)(81). Notably, in some of the animal models in which the OT treatment was successful, a dysregulation of the OT/OTR system was concomitantly reported.…”

Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration

“…18,27]. Although alterations of the endogenous oxytocin system have been previously demonstrated following acute or chronic alcohol [28], cocaine [16,17,29], methamphetamine [18], 3,4-methylenedioxymethamphetamine (MDMA) [30] and morphine [19,31,32] administration in the brain of rodents, this is the first study to report central oxytocinergic neuroadaptations following chronic nicotine administration.…”