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Dopamine D3 Receptor Mediates Preadolescent Stress-Induced Adult Psychiatric Disorders.

Seo JH, Kuzhikandathil EV - PLoS ONE (2015)

Bottom Line: We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood.In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus.Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Physiology and Neurosciences, Rutgers-New Jersey Medical School, Newark, NJ, 07103, United States of America.

ABSTRACT
Several studies have shown that repeated stressful experiences during childhood increases the likelihood of developing depression- and anxiety-related disorders in adulthood; however, the underlying mechanisms are not well understood. We subjected drd3-EGFP and drd3- mice to daily, two hour restraint stress episodes over a five day period during preadolescence (postnatal day 35 to 39), followed by social isolation. When these mice reached adulthood (post-natal day > 90), we assessed locomotor behavior in a novel environment, and assessed depression-related behavior in the Porsolt Forced Swim test. We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood. Adult male mice subjected to restraint stress during preadolescence exhibited both anxiety- and depression-related behaviors; however, adult female mice subjected to preadolescent restraint stress exhibited only depression-related behaviors. The development of preadolescent stress-derived psychiatric disorders was blocked by D3 receptor selective antagonist, SB 277011-A, and absent in D3 receptor mice. Adult male mice that experienced stress during preadolescence exhibited a loss of D3 receptor expression and function in the amygdala but not in hippocampus or nucleus accumbens. In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus. Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood.

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Effect of repeated restraint stress and social isolation during preadolescence on number of center zone entries in an open field arena by adult drd3-EGFP mice.Adult male (A and B) and female (C and D) drd3-EGFP mice were either not stressed (blue, n = 11) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 11). Number of center zone entries were measured in an Open Field test in adulthood. Significant reduction in number of entries was observed in stressed male drd3-EGFP mice during the initial 20 minute period following the placement of the mice in the arena (*, p<0.05, two-way repeated measure ANOVA, post-hoc SNK test; A). The total number of center zone entries over the entire 60 minute observation period was also significantly reduced in stressed male drd3-EGFP mice (*, p<0.05, Student’s t-test). The stress-induced changes in locomotor activity was absent in adult female drd3-EGFP mice subjected to preadolescent stress and social isolation (C and D). Error bars represents ± SEM.
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pone.0143908.g002: Effect of repeated restraint stress and social isolation during preadolescence on number of center zone entries in an open field arena by adult drd3-EGFP mice.Adult male (A and B) and female (C and D) drd3-EGFP mice were either not stressed (blue, n = 11) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 11). Number of center zone entries were measured in an Open Field test in adulthood. Significant reduction in number of entries was observed in stressed male drd3-EGFP mice during the initial 20 minute period following the placement of the mice in the arena (*, p<0.05, two-way repeated measure ANOVA, post-hoc SNK test; A). The total number of center zone entries over the entire 60 minute observation period was also significantly reduced in stressed male drd3-EGFP mice (*, p<0.05, Student’s t-test). The stress-induced changes in locomotor activity was absent in adult female drd3-EGFP mice subjected to preadolescent stress and social isolation (C and D). Error bars represents ± SEM.

Mentions: Male drd3-EGFP mice that were subjected to preadolescent repetitive restraint stress followed by social isolation exhibited, in adulthood, a significant reduction in number of center zone entries in a novel arena (p = 0.043, F1,220 = 4.772, two-way repeated measure ANOVA; Fig 2A) wherein, post-hoc SNK test revealed significant difference between the non-stressed and stressed mice only at the 10 min (q = 3.647, p = 0.013), 15 min (q = 4.137, p = 0.005) and 20 min (q = 3.647, p = 0.013) time points. No significant difference in basal center zone entries was observed during the initial 5 min period after the mice were placed in the novel arena (q = 1.959, p = 0.171). The large decrease in center zone entries during the 10 to 20 min interval resulted in an overall decrease in number of center zone entries over the 60 minute monitoring period (p = 0.043, Student’s t-test; Fig 2B). Female drd3-EGFP mice that were subjected to preadolescent repetitive restraint stress followed by social isolation did not exhibit, in adulthood, a significant reduction in number of center zone entries in a novel environment (p = 0.222, F1,165 = 1.635, two-way repeated measure ANOVA; Fig 2C) and, post-hoc SNK test did not reveal significant difference between the non-stressed and stressed mice at any time points. There was also no significant difference in number of center zone entries during the entire 60 minute monitoring period (p = 0.222, Student’s t-test; Fig 2D). Comparison of non-stressed male and female drd3-EGFP mice showed that the female drd3-EGFP mice exhibited a significantly greater number of center zone entries (Fig 2). The transient reduction of locomotor activity in a novel environment and decrease in number of center zone entries in an Open Field test that we observed here in the stressed male drd3-EGFP mice is considered an endophenotype of anxiety-related behavior in rodent models according to previous studies [27]. Together the results in Figs 1 and 2, suggest that repetitive restraint stress followed by social isolation during preadolescence results in the development of anxiety-related behaviors in adulthood, specifically in male mice.


Dopamine D3 Receptor Mediates Preadolescent Stress-Induced Adult Psychiatric Disorders.

Seo JH, Kuzhikandathil EV - PLoS ONE (2015)

Effect of repeated restraint stress and social isolation during preadolescence on number of center zone entries in an open field arena by adult drd3-EGFP mice.Adult male (A and B) and female (C and D) drd3-EGFP mice were either not stressed (blue, n = 11) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 11). Number of center zone entries were measured in an Open Field test in adulthood. Significant reduction in number of entries was observed in stressed male drd3-EGFP mice during the initial 20 minute period following the placement of the mice in the arena (*, p<0.05, two-way repeated measure ANOVA, post-hoc SNK test; A). The total number of center zone entries over the entire 60 minute observation period was also significantly reduced in stressed male drd3-EGFP mice (*, p<0.05, Student’s t-test). The stress-induced changes in locomotor activity was absent in adult female drd3-EGFP mice subjected to preadolescent stress and social isolation (C and D). Error bars represents ± SEM.
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getmorefigures.php?uid=PMC4664486&req=5

pone.0143908.g002: Effect of repeated restraint stress and social isolation during preadolescence on number of center zone entries in an open field arena by adult drd3-EGFP mice.Adult male (A and B) and female (C and D) drd3-EGFP mice were either not stressed (blue, n = 11) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 11). Number of center zone entries were measured in an Open Field test in adulthood. Significant reduction in number of entries was observed in stressed male drd3-EGFP mice during the initial 20 minute period following the placement of the mice in the arena (*, p<0.05, two-way repeated measure ANOVA, post-hoc SNK test; A). The total number of center zone entries over the entire 60 minute observation period was also significantly reduced in stressed male drd3-EGFP mice (*, p<0.05, Student’s t-test). The stress-induced changes in locomotor activity was absent in adult female drd3-EGFP mice subjected to preadolescent stress and social isolation (C and D). Error bars represents ± SEM.
Mentions: Male drd3-EGFP mice that were subjected to preadolescent repetitive restraint stress followed by social isolation exhibited, in adulthood, a significant reduction in number of center zone entries in a novel arena (p = 0.043, F1,220 = 4.772, two-way repeated measure ANOVA; Fig 2A) wherein, post-hoc SNK test revealed significant difference between the non-stressed and stressed mice only at the 10 min (q = 3.647, p = 0.013), 15 min (q = 4.137, p = 0.005) and 20 min (q = 3.647, p = 0.013) time points. No significant difference in basal center zone entries was observed during the initial 5 min period after the mice were placed in the novel arena (q = 1.959, p = 0.171). The large decrease in center zone entries during the 10 to 20 min interval resulted in an overall decrease in number of center zone entries over the 60 minute monitoring period (p = 0.043, Student’s t-test; Fig 2B). Female drd3-EGFP mice that were subjected to preadolescent repetitive restraint stress followed by social isolation did not exhibit, in adulthood, a significant reduction in number of center zone entries in a novel environment (p = 0.222, F1,165 = 1.635, two-way repeated measure ANOVA; Fig 2C) and, post-hoc SNK test did not reveal significant difference between the non-stressed and stressed mice at any time points. There was also no significant difference in number of center zone entries during the entire 60 minute monitoring period (p = 0.222, Student’s t-test; Fig 2D). Comparison of non-stressed male and female drd3-EGFP mice showed that the female drd3-EGFP mice exhibited a significantly greater number of center zone entries (Fig 2). The transient reduction of locomotor activity in a novel environment and decrease in number of center zone entries in an Open Field test that we observed here in the stressed male drd3-EGFP mice is considered an endophenotype of anxiety-related behavior in rodent models according to previous studies [27]. Together the results in Figs 1 and 2, suggest that repetitive restraint stress followed by social isolation during preadolescence results in the development of anxiety-related behaviors in adulthood, specifically in male mice.

Bottom Line: We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood.In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus.Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Physiology and Neurosciences, Rutgers-New Jersey Medical School, Newark, NJ, 07103, United States of America.

ABSTRACT
Several studies have shown that repeated stressful experiences during childhood increases the likelihood of developing depression- and anxiety-related disorders in adulthood; however, the underlying mechanisms are not well understood. We subjected drd3-EGFP and drd3- mice to daily, two hour restraint stress episodes over a five day period during preadolescence (postnatal day 35 to 39), followed by social isolation. When these mice reached adulthood (post-natal day > 90), we assessed locomotor behavior in a novel environment, and assessed depression-related behavior in the Porsolt Forced Swim test. We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood. Adult male mice subjected to restraint stress during preadolescence exhibited both anxiety- and depression-related behaviors; however, adult female mice subjected to preadolescent restraint stress exhibited only depression-related behaviors. The development of preadolescent stress-derived psychiatric disorders was blocked by D3 receptor selective antagonist, SB 277011-A, and absent in D3 receptor mice. Adult male mice that experienced stress during preadolescence exhibited a loss of D3 receptor expression and function in the amygdala but not in hippocampus or nucleus accumbens. In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus. Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood.

Show MeSH
Related in: MedlinePlus