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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

Regional distribution and quantification of OXTR in WT mice. Average regional expression of OXTR defined by [125I]-OVTA binding in WT mice. For each animal, final levels of OXTR expression were calculated averaging data obtained from the different coronal planes analyzed within the same region of interest. Each bar represents data expressed as mean and SEM of four animals.
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Figure 2: Regional distribution and quantification of OXTR in WT mice. Average regional expression of OXTR defined by [125I]-OVTA binding in WT mice. For each animal, final levels of OXTR expression were calculated averaging data obtained from the different coronal planes analyzed within the same region of interest. Each bar represents data expressed as mean and SEM of four animals.

Mentions: The use of a commercial 125I microscales standard allowed us to quantify the levels of [125I]-OVTA binding in the brain of our mice. Quantification of OXTR expression in several areas of the brain in WT mice is reported in Figure 2. In WT mice, we found the highest levels of OXTR (here in the text reported as mean nanocurie per milligram tissue equivalent ± SD) in the olfactory bulb (OB, 0.91 ± 0.25), the AON (0.88 ± 0.22), and in some posterior nuclei of the amygdala, specifically 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). Medium level of OVTA binding was detected in lateral septum (LS, 0.41 ± 0.06), the bed nucleus of the stria terminalis (BNST, 0.34 ± 0.06), the CA3 field of the hippocampus (Hipp CA3, 0.30 ± 0.06), the paraventricular thalamic nucleus (PV, 0.32 ± 0.06), and in the medial amygdaloid nucleus (MeA, 0.26 ± 0.04). In the other anterior nuclei of the amygdala analyzed, the CeA nucleus (0.16 ± 0.05) and the anterior part of the basolateral amygdaloid nucleus (BLA, 0.18 ± 0.04), and in the NAcc (0.10 ± 0.04) OXTR expression was rather low. Interestingly, Dölen et al. (33) report the basolateral nucleus of the amygdala as a whole to display “average” OXTR expression, however, from observation during analysis we noticed a clear difference in OXTR expression between the anterior and the posterior parts of this nucleus, therefore, we deemed it more appropriate to analyze the two subregions separately, distinguishing them into BLA and BLP. Finally, we found minimal expression of OXTR in the CPu (0.02 ± 0.02) and the habenula (Hb, 0.04 ± 0.02) of WT mice. Overall, the expression and the distribution of OXTR in the brains of WT mice, at least in relation to the regions analyzed, is consistent with what has been previously reported (see Table 1).


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)

Regional distribution and quantification of OXTR in WT mice. Average regional expression of OXTR defined by [125I]-OVTA binding in WT mice. For each animal, final levels of OXTR expression were calculated averaging data obtained from the different coronal planes analyzed within the same region of interest. Each bar represents data expressed as mean and SEM of four animals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Regional distribution and quantification of OXTR in WT mice. Average regional expression of OXTR defined by [125I]-OVTA binding in WT mice. For each animal, final levels of OXTR expression were calculated averaging data obtained from the different coronal planes analyzed within the same region of interest. Each bar represents data expressed as mean and SEM of four animals.
Mentions: The use of a commercial 125I microscales standard allowed us to quantify the levels of [125I]-OVTA binding in the brain of our mice. Quantification of OXTR expression in several areas of the brain in WT mice is reported in Figure 2. In WT mice, we found the highest levels of OXTR (here in the text reported as mean nanocurie per milligram tissue equivalent ± SD) in the olfactory bulb (OB, 0.91 ± 0.25), the AON (0.88 ± 0.22), and in some posterior nuclei of the amygdala, specifically 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). Medium level of OVTA binding was detected in lateral septum (LS, 0.41 ± 0.06), the bed nucleus of the stria terminalis (BNST, 0.34 ± 0.06), the CA3 field of the hippocampus (Hipp CA3, 0.30 ± 0.06), the paraventricular thalamic nucleus (PV, 0.32 ± 0.06), and in the medial amygdaloid nucleus (MeA, 0.26 ± 0.04). In the other anterior nuclei of the amygdala analyzed, the CeA nucleus (0.16 ± 0.05) and the anterior part of the basolateral amygdaloid nucleus (BLA, 0.18 ± 0.04), and in the NAcc (0.10 ± 0.04) OXTR expression was rather low. Interestingly, Dölen et al. (33) report the basolateral nucleus of the amygdala as a whole to display “average” OXTR expression, however, from observation during analysis we noticed a clear difference in OXTR expression between the anterior and the posterior parts of this nucleus, therefore, we deemed it more appropriate to analyze the two subregions separately, distinguishing them into BLA and BLP. Finally, we found minimal expression of OXTR in the CPu (0.02 ± 0.02) and the habenula (Hb, 0.04 ± 0.02) of WT mice. Overall, the expression and the distribution of OXTR in the brains of WT mice, at least in relation to the regions analyzed, is consistent with what has been previously reported (see Table 1).

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