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Region specific up-regulation of oxytocin receptors in the opioid oprm1 (-/-) mouse model of autism.

Gigliucci V, Leonzino M, Busnelli M, Luchetti A, Palladino VS, D'Amato FR, Chini B - Front Pediatr (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience, National Research Council , Milan , Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Oprm1−/− mice display increased OXTR expression in the medial AON and the nucleus accumbens. Average regional expression of OXTR defined by [125I]-OVTA binding in Oprm1−/− mice in comparison with WT mice. OXTR expression is increased in both (A) AONm and (B) NAcc of Oprm1−/− mice. At the zone of transition between AON and NAcc, distinction between the two structures was determined by AChE staining, which selectively labels the NAcc and the olfactory tubercle. (C) The spot of intense [125I]-OVTA labeling evident in the autoradiographic picture and the AChE staining, apparently in the same position, do not overlap when the two images are merged (blow-up), indicating that the NAcc doesn’t express high levels of OXTR in this area. (D) Superimposition of the autoradiogram and the AChE staining of a coronal section of the NAcc where the AONm is not present anymore (blow-up) confirms that this region does not express high levels of OXTR.
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Figure 4: Oprm1−/− mice display increased OXTR expression in the medial AON and the nucleus accumbens. Average regional expression of OXTR defined by [125I]-OVTA binding in Oprm1−/− mice in comparison with WT mice. OXTR expression is increased in both (A) AONm and (B) NAcc of Oprm1−/− mice. At the zone of transition between AON and NAcc, distinction between the two structures was determined by AChE staining, which selectively labels the NAcc and the olfactory tubercle. (C) The spot of intense [125I]-OVTA labeling evident in the autoradiographic picture and the AChE staining, apparently in the same position, do not overlap when the two images are merged (blow-up), indicating that the NAcc doesn’t express high levels of OXTR in this area. (D) Superimposition of the autoradiogram and the AChE staining of a coronal section of the NAcc where the AONm is not present anymore (blow-up) confirms that this region does not express high levels of OXTR.

Mentions: Another region in which we found an up-regulation of OXTR is the AONm in the posterior part of AON {t-test; [t(7) = 3.590, p < 0.01]} (Figure 4A). Because discriminating between the AON and NAcc is particularly tricky in this area of the brain, we performed AChE staining on the same slices processed for autoradiography. AChE selectively labels the NAcc and the olfactory tubercle but not the AON, thus allowing unambiguous identification of the two structures. Figures 4C,D show examples of brain sections labeled with [125I]-OVTA and AChE. In the blow-ups of the merged images it is evident that the strong autoradiographic signal observed in this area does not overlap with the AChE staining, but it is adjacent to it. This allowed us to assign the strong specific [125I]-OVTA labeling of this region to the AONm. Given the difficulty, in this region, to discriminate between AONm and NAcc in absence of AChE staining, we cannot exclude that the area identified as NAcc in (34) may, instead, correspond to the AONm.


Region specific up-regulation of oxytocin receptors in the opioid oprm1 (-/-) mouse model of autism.

Gigliucci V, Leonzino M, Busnelli M, Luchetti A, Palladino VS, D'Amato FR, Chini B - Front Pediatr (2014)

Oprm1−/− mice display increased OXTR expression in the medial AON and the nucleus accumbens. Average regional expression of OXTR defined by [125I]-OVTA binding in Oprm1−/− mice in comparison with WT mice. OXTR expression is increased in both (A) AONm and (B) NAcc of Oprm1−/− mice. At the zone of transition between AON and NAcc, distinction between the two structures was determined by AChE staining, which selectively labels the NAcc and the olfactory tubercle. (C) The spot of intense [125I]-OVTA labeling evident in the autoradiographic picture and the AChE staining, apparently in the same position, do not overlap when the two images are merged (blow-up), indicating that the NAcc doesn’t express high levels of OXTR in this area. (D) Superimposition of the autoradiogram and the AChE staining of a coronal section of the NAcc where the AONm is not present anymore (blow-up) confirms that this region does not express high levels of OXTR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150055&req=5

Figure 4: Oprm1−/− mice display increased OXTR expression in the medial AON and the nucleus accumbens. Average regional expression of OXTR defined by [125I]-OVTA binding in Oprm1−/− mice in comparison with WT mice. OXTR expression is increased in both (A) AONm and (B) NAcc of Oprm1−/− mice. At the zone of transition between AON and NAcc, distinction between the two structures was determined by AChE staining, which selectively labels the NAcc and the olfactory tubercle. (C) The spot of intense [125I]-OVTA labeling evident in the autoradiographic picture and the AChE staining, apparently in the same position, do not overlap when the two images are merged (blow-up), indicating that the NAcc doesn’t express high levels of OXTR in this area. (D) Superimposition of the autoradiogram and the AChE staining of a coronal section of the NAcc where the AONm is not present anymore (blow-up) confirms that this region does not express high levels of OXTR.
Mentions: Another region in which we found an up-regulation of OXTR is the AONm in the posterior part of AON {t-test; [t(7) = 3.590, p < 0.01]} (Figure 4A). Because discriminating between the AON and NAcc is particularly tricky in this area of the brain, we performed AChE staining on the same slices processed for autoradiography. AChE selectively labels the NAcc and the olfactory tubercle but not the AON, thus allowing unambiguous identification of the two structures. Figures 4C,D show examples of brain sections labeled with [125I]-OVTA and AChE. In the blow-ups of the merged images it is evident that the strong autoradiographic signal observed in this area does not overlap with the AChE staining, but it is adjacent to it. This allowed us to assign the strong specific [125I]-OVTA labeling of this region to the AONm. Given the difficulty, in this region, to discriminate between AONm and NAcc in absence of AChE staining, we cannot exclude that the area identified as NAcc in (34) may, instead, correspond to the AONm.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience, National Research Council , Milan , Italy.

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.

No MeSH data available.


Related in: MedlinePlus