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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

Acute intranasal administration of OXT rescues the impairments in ultrasound emission in Oprm1−/− mice during male–female social interaction. Effects of acute intranasal OXT administration (600 ng) in Oprm1−/− and WT male mice during a 5 min male–female social interaction. (A) Genotype and OXT treatment do not affect the amount of time spent in locomotion, exploration, self-grooming, or social investigation during the test. (B)Oprm1−/− mice emit a reduced number of ultrasound vocalizations during the test in comparison with WT mice, and this deficit is completely rescued by OXT treatment. Data expressed as mean and SEM of eight to nine animals. *p < 0.05, **p < 0.01 compared to Oprm1−/− + veh group.
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Figure 5: Acute intranasal administration of OXT rescues the impairments in ultrasound emission in Oprm1−/− mice during male–female social interaction. Effects of acute intranasal OXT administration (600 ng) in Oprm1−/− and WT male mice during a 5 min male–female social interaction. (A) Genotype and OXT treatment do not affect the amount of time spent in locomotion, exploration, self-grooming, or social investigation during the test. (B)Oprm1−/− mice emit a reduced number of ultrasound vocalizations during the test in comparison with WT mice, and this deficit is completely rescued by OXT treatment. Data expressed as mean and SEM of eight to nine animals. *p < 0.05, **p < 0.01 compared to Oprm1−/− + veh group.

Mentions: To evaluate the pro-social effects of OXT, we tested sexually naive males during courtship, before the initiation of sexual behavior, during the first minutes of interaction with a female. The behavioral profile of males interacting with females is shown in Figure 5. The MANOVA indicated no significant effect of main factors (genotype: λ = 0.90, F(5/27) = 0.58, n.s.; treatment: λ = 0.89, F(5/27) = 0.61, n.s.), but a significant genotype × treatment interaction (λ = 0.62, F(5/27) = 3.56, p < 0.05), suggesting that OXT had different effect on mice behavioral profile according to the genotype. Univariate results confirmed significant genotype × treatment effect for locomotion [F(1/31) = 5.01, p < 0.05], social investigation [F(1/31) = 4.22, p < 0.05], and USVs [F(1/31) = 15.29, p < 0.001]. Post hoc analysis showed a significant difference at basal conditions between Oprm1−/− and WT mice only in ultrasonic vocalizations (Oprm1−/− + Veh vs. WT + Veh: p < 0.01), and an increase in the number of USVs due to OXT treatment, selectively in the Oprm1−/− line (Oprm1−/− + Veh vs. Oprm1−/− + OXT: p = 0.01). By contrast, OXT did not to significantly modify WT males’ vocalizations (p = 0.13, n.s.) (Figure 5B). The deficit shown by Oprm1−/− mice in USVs emission in response to social cues does not depend on a general impairment in their capacity to emit high levels of ultrasonic calls or in their sensitivity to olfactory stimuli, in infancy (16) as well as in adulthood (data presented here), but suggests lower motivation to interact with conspecifics.


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)

Acute intranasal administration of OXT rescues the impairments in ultrasound emission in Oprm1−/− mice during male–female social interaction. Effects of acute intranasal OXT administration (600 ng) in Oprm1−/− and WT male mice during a 5 min male–female social interaction. (A) Genotype and OXT treatment do not affect the amount of time spent in locomotion, exploration, self-grooming, or social investigation during the test. (B)Oprm1−/− mice emit a reduced number of ultrasound vocalizations during the test in comparison with WT mice, and this deficit is completely rescued by OXT treatment. Data expressed as mean and SEM of eight to nine animals. *p < 0.05, **p < 0.01 compared to Oprm1−/− + veh group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Acute intranasal administration of OXT rescues the impairments in ultrasound emission in Oprm1−/− mice during male–female social interaction. Effects of acute intranasal OXT administration (600 ng) in Oprm1−/− and WT male mice during a 5 min male–female social interaction. (A) Genotype and OXT treatment do not affect the amount of time spent in locomotion, exploration, self-grooming, or social investigation during the test. (B)Oprm1−/− mice emit a reduced number of ultrasound vocalizations during the test in comparison with WT mice, and this deficit is completely rescued by OXT treatment. Data expressed as mean and SEM of eight to nine animals. *p < 0.05, **p < 0.01 compared to Oprm1−/− + veh group.
Mentions: To evaluate the pro-social effects of OXT, we tested sexually naive males during courtship, before the initiation of sexual behavior, during the first minutes of interaction with a female. The behavioral profile of males interacting with females is shown in Figure 5. The MANOVA indicated no significant effect of main factors (genotype: λ = 0.90, F(5/27) = 0.58, n.s.; treatment: λ = 0.89, F(5/27) = 0.61, n.s.), but a significant genotype × treatment interaction (λ = 0.62, F(5/27) = 3.56, p < 0.05), suggesting that OXT had different effect on mice behavioral profile according to the genotype. Univariate results confirmed significant genotype × treatment effect for locomotion [F(1/31) = 5.01, p < 0.05], social investigation [F(1/31) = 4.22, p < 0.05], and USVs [F(1/31) = 15.29, p < 0.001]. Post hoc analysis showed a significant difference at basal conditions between Oprm1−/− and WT mice only in ultrasonic vocalizations (Oprm1−/− + Veh vs. WT + Veh: p < 0.01), and an increase in the number of USVs due to OXT treatment, selectively in the Oprm1−/− line (Oprm1−/− + Veh vs. Oprm1−/− + OXT: p = 0.01). By contrast, OXT did not to significantly modify WT males’ vocalizations (p = 0.13, n.s.) (Figure 5B). The deficit shown by Oprm1−/− mice in USVs emission in response to social cues does not depend on a general impairment in their capacity to emit high levels of ultrasonic calls or in their sensitivity to olfactory stimuli, in infancy (16) as well as in adulthood (data presented here), but suggests lower motivation to interact with conspecifics.

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