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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 locomotor activity in an open field arena test by adult drd3- mice.Adult male (A and B) and female (C and D) drd3- mice were either not stressed (blue, n = 5) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 5). Horizontal locomotor activity were measured in an Open Field test in adulthood. Compared to non-stressed drd3- male mice, preadolescent stressed male drd3- mice exhibited significant increase in locomotor activity (A) only during the initial 15 minute period following the placement of the mice in the arena (*, p<0.05, two-way repeated measure ANOVA, post-hoc SNK test). The total locomotor activity over the entire 60 minute observation period was not significantly altered in stressed male drd3- mice (p>0.05, Student’s t-test). The stress-induced changes in locomotor activity was absent in adult female drd3- mice subjected to preadolescent stress and social isolation (C and D). Error bars represents ± SEM.
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pone.0143908.g003: Effect of repeated restraint stress and social isolation during preadolescence on locomotor activity in an open field arena test by adult drd3- mice.Adult male (A and B) and female (C and D) drd3- mice were either not stressed (blue, n = 5) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 5). Horizontal locomotor activity were measured in an Open Field test in adulthood. Compared to non-stressed drd3- male mice, preadolescent stressed male drd3- mice exhibited significant increase in locomotor activity (A) only during the initial 15 minute period following the placement of the mice in the arena (*, p<0.05, two-way repeated measure ANOVA, post-hoc SNK test). The total locomotor activity over the entire 60 minute observation period was not significantly altered in stressed male drd3- mice (p>0.05, Student’s t-test). The stress-induced changes in locomotor activity was absent in adult female drd3- mice subjected to preadolescent stress and social isolation (C and D). Error bars represents ± SEM.

Mentions: To determine the role of dopamine D3 receptor in preadolescent stress-induced adult anxiety-related disorders, we subjected male and female drd3 mice to the preadolescent restraint stress and social isolation protocol and assessed anxiety-related behaviors in adulthood. Male drd3 mice, lacking the dopamine D3 receptor gene, that were subjected to the preadolescent stress and social isolation (Fig 3A and 3B) did not show a significant reduction in locomotor activity in the Open Field test (p = 0.093, F1,88 = 3.644, two-way repeated measure ANOVA; Fig 3A). However, post-hoc SNK test revealed significant increase in locomotor activity of stressed mice only at the 5 min (q = 4.134, p = 0.007), 10 min (q = 3.762, p = 0.014) and 15 min (q = 3.225, p = 0.032) time points. There was also no significant difference in locomotor activity of the male drd3 mice during the entire 60 minute monitoring period (p = 0.093, Student’s t-test; Fig 3B). Female drd3- mice that were subjected to preadolescent repetitive restraint stress followed by social isolation did not exhibit, in adulthood, a significant change in locomotor activity in a novel environment (p = 0.454, F1,88 = 0.618, two-way repeated measure ANOVA; Fig 3C) 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 locomotor activity during the entire 60 minute monitoring period (p = 0.454, Student’s t-test; Fig 3D).


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 locomotor activity in an open field arena test by adult drd3- mice.Adult male (A and B) and female (C and D) drd3- mice were either not stressed (blue, n = 5) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 5). Horizontal locomotor activity were measured in an Open Field test in adulthood. Compared to non-stressed drd3- male mice, preadolescent stressed male drd3- mice exhibited significant increase in locomotor activity (A) only during the initial 15 minute period following the placement of the mice in the arena (*, p<0.05, two-way repeated measure ANOVA, post-hoc SNK test). The total locomotor activity over the entire 60 minute observation period was not significantly altered in stressed male drd3- mice (p>0.05, Student’s t-test). The stress-induced changes in locomotor activity was absent in adult female drd3- mice subjected to preadolescent stress and social isolation (C and D). Error bars represents ± SEM.
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pone.0143908.g003: Effect of repeated restraint stress and social isolation during preadolescence on locomotor activity in an open field arena test by adult drd3- mice.Adult male (A and B) and female (C and D) drd3- mice were either not stressed (blue, n = 5) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 5). Horizontal locomotor activity were measured in an Open Field test in adulthood. Compared to non-stressed drd3- male mice, preadolescent stressed male drd3- mice exhibited significant increase in locomotor activity (A) only during the initial 15 minute period following the placement of the mice in the arena (*, p<0.05, two-way repeated measure ANOVA, post-hoc SNK test). The total locomotor activity over the entire 60 minute observation period was not significantly altered in stressed male drd3- mice (p>0.05, Student’s t-test). The stress-induced changes in locomotor activity was absent in adult female drd3- mice subjected to preadolescent stress and social isolation (C and D). Error bars represents ± SEM.
Mentions: To determine the role of dopamine D3 receptor in preadolescent stress-induced adult anxiety-related disorders, we subjected male and female drd3 mice to the preadolescent restraint stress and social isolation protocol and assessed anxiety-related behaviors in adulthood. Male drd3 mice, lacking the dopamine D3 receptor gene, that were subjected to the preadolescent stress and social isolation (Fig 3A and 3B) did not show a significant reduction in locomotor activity in the Open Field test (p = 0.093, F1,88 = 3.644, two-way repeated measure ANOVA; Fig 3A). However, post-hoc SNK test revealed significant increase in locomotor activity of stressed mice only at the 5 min (q = 4.134, p = 0.007), 10 min (q = 3.762, p = 0.014) and 15 min (q = 3.225, p = 0.032) time points. There was also no significant difference in locomotor activity of the male drd3 mice during the entire 60 minute monitoring period (p = 0.093, Student’s t-test; Fig 3B). Female drd3- mice that were subjected to preadolescent repetitive restraint stress followed by social isolation did not exhibit, in adulthood, a significant change in locomotor activity in a novel environment (p = 0.454, F1,88 = 0.618, two-way repeated measure ANOVA; Fig 3C) 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 locomotor activity during the entire 60 minute monitoring period (p = 0.454, Student’s t-test; Fig 3D).

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