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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 function and expression of dopamine D3 receptors in three limbic brain regions of adult male drd3-EGFP mice.Male drd3-EGFP mice (A-D, n = 5 per treatment group) were either not stressed (blue) or subjected to preadolescent restraint stress and social isolation (red). In adulthood, the two groups of mice were administered saline or 0.05 mg/kg PD128907, s.c., a D3 receptor agonist. The three brain regions nucleus accumbens (A), hippocampus (B) and amygdala (C and D) were harvested ten minutes after the injection. The levels of phosphorylated ERK and total ERK were measured using western blot and expressed as a ratio (A-C). A significant increase in PD128907-induced ERK phosphorylation was observed in the nucleus accumbens and hippocampus of non-stressed and stressed mice but only in the amygdala of non-stressed mice (*, p<0.05). There was also a significant reduction of D3 receptor protein levels in the amygdala of stressed mice (D, # p<0.05). Error bars represents ± SEM.
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pone.0143908.g009: Effect of repeated restraint stress and social isolation during preadolescence on function and expression of dopamine D3 receptors in three limbic brain regions of adult male drd3-EGFP mice.Male drd3-EGFP mice (A-D, n = 5 per treatment group) were either not stressed (blue) or subjected to preadolescent restraint stress and social isolation (red). In adulthood, the two groups of mice were administered saline or 0.05 mg/kg PD128907, s.c., a D3 receptor agonist. The three brain regions nucleus accumbens (A), hippocampus (B) and amygdala (C and D) were harvested ten minutes after the injection. The levels of phosphorylated ERK and total ERK were measured using western blot and expressed as a ratio (A-C). A significant increase in PD128907-induced ERK phosphorylation was observed in the nucleus accumbens and hippocampus of non-stressed and stressed mice but only in the amygdala of non-stressed mice (*, p<0.05). There was also a significant reduction of D3 receptor protein levels in the amygdala of stressed mice (D, # p<0.05). Error bars represents ± SEM.

Mentions: Next, we compared the signaling function of dopamine D3 receptor in adult male non-stressed and stressed drd3-EGFP mice in nucleus accumbens, hippocampus and amygdala. We have previously shown that 0.05 mg/kg PD128907 selectively activates the D3 receptor-mitogen activated protein kinase signaling pathway in drd3-EGFP mice resulting in increased phosphorylated ERK protein levels [13]. The results in Fig 9 show that while activation of MAPK pathway by D3 receptor in the nucleus accumbens (Fig 9A; p<0.001, F1,16 = 19.646, two-way ANOVA, post-hoc SNK test) and hippocampus (Fig 9B;; p = 0.001, F1,14 = 17.03, two-way ANOVA, post-hoc SNK test) is unaffected by preadolescent stress, there is a loss of D3 receptor-MAPK signaling function in the amygdala of adult male drd3-EGFP mice that were subjected to preadolescent repetitive restraint stress and social isolation (Fig 9C; p = 0.953, q = 0.09, two-way ANOVA, post-hoc SNK test). This loss of D3 receptor signaling function in the amygdala correlated with a significant decrease in D3 receptor protein expression in the amygdala of adult male drd3-EGFP mice subjected to preadolescent stress and social isolation (Fig 9D; p<0.001, Student’s t-test). Given our observation that preadolescence stress and social isolation caused anxiety- and depression-related disorders in adult male mice but only depression-related disorders in adult female mice, we measured the expression of dopamine D3 receptor in control and stressed adult female drd3-EGFP mice in amygdala, hippocampus and nucleus accumbens (Fig 10). Interestingly, the result showed no difference in D3 receptor expression in the amygdala or hippocampus (Fig 10A and 10B); however, there was a significant increase in D3 receptor expression in the nucleus accumbens of female mice (p<0.01, Student’s t-test; Fig 10C and S2 Fig) and no change in D3 receptor expression in nucleus accumbens of male mice (Fig 10D). Together these results suggest that the decrease of D3 receptor expression and loss of D3 receptor signaling function in the amygdala might contribute to the adult anxiety- and depression-related behaviors in male mice that were subjected to preadolescent stress and social isolation. In contrast, an increase in expression of D3 receptor in the nucleus accumbens of female mice subjected to preadolescent stress and social isolation might contribute to depression-related disorders in adulthood.


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 function and expression of dopamine D3 receptors in three limbic brain regions of adult male drd3-EGFP mice.Male drd3-EGFP mice (A-D, n = 5 per treatment group) were either not stressed (blue) or subjected to preadolescent restraint stress and social isolation (red). In adulthood, the two groups of mice were administered saline or 0.05 mg/kg PD128907, s.c., a D3 receptor agonist. The three brain regions nucleus accumbens (A), hippocampus (B) and amygdala (C and D) were harvested ten minutes after the injection. The levels of phosphorylated ERK and total ERK were measured using western blot and expressed as a ratio (A-C). A significant increase in PD128907-induced ERK phosphorylation was observed in the nucleus accumbens and hippocampus of non-stressed and stressed mice but only in the amygdala of non-stressed mice (*, p<0.05). There was also a significant reduction of D3 receptor protein levels in the amygdala of stressed mice (D, # p<0.05). Error bars represents ± SEM.
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pone.0143908.g009: Effect of repeated restraint stress and social isolation during preadolescence on function and expression of dopamine D3 receptors in three limbic brain regions of adult male drd3-EGFP mice.Male drd3-EGFP mice (A-D, n = 5 per treatment group) were either not stressed (blue) or subjected to preadolescent restraint stress and social isolation (red). In adulthood, the two groups of mice were administered saline or 0.05 mg/kg PD128907, s.c., a D3 receptor agonist. The three brain regions nucleus accumbens (A), hippocampus (B) and amygdala (C and D) were harvested ten minutes after the injection. The levels of phosphorylated ERK and total ERK were measured using western blot and expressed as a ratio (A-C). A significant increase in PD128907-induced ERK phosphorylation was observed in the nucleus accumbens and hippocampus of non-stressed and stressed mice but only in the amygdala of non-stressed mice (*, p<0.05). There was also a significant reduction of D3 receptor protein levels in the amygdala of stressed mice (D, # p<0.05). Error bars represents ± SEM.
Mentions: Next, we compared the signaling function of dopamine D3 receptor in adult male non-stressed and stressed drd3-EGFP mice in nucleus accumbens, hippocampus and amygdala. We have previously shown that 0.05 mg/kg PD128907 selectively activates the D3 receptor-mitogen activated protein kinase signaling pathway in drd3-EGFP mice resulting in increased phosphorylated ERK protein levels [13]. The results in Fig 9 show that while activation of MAPK pathway by D3 receptor in the nucleus accumbens (Fig 9A; p<0.001, F1,16 = 19.646, two-way ANOVA, post-hoc SNK test) and hippocampus (Fig 9B;; p = 0.001, F1,14 = 17.03, two-way ANOVA, post-hoc SNK test) is unaffected by preadolescent stress, there is a loss of D3 receptor-MAPK signaling function in the amygdala of adult male drd3-EGFP mice that were subjected to preadolescent repetitive restraint stress and social isolation (Fig 9C; p = 0.953, q = 0.09, two-way ANOVA, post-hoc SNK test). This loss of D3 receptor signaling function in the amygdala correlated with a significant decrease in D3 receptor protein expression in the amygdala of adult male drd3-EGFP mice subjected to preadolescent stress and social isolation (Fig 9D; p<0.001, Student’s t-test). Given our observation that preadolescence stress and social isolation caused anxiety- and depression-related disorders in adult male mice but only depression-related disorders in adult female mice, we measured the expression of dopamine D3 receptor in control and stressed adult female drd3-EGFP mice in amygdala, hippocampus and nucleus accumbens (Fig 10). Interestingly, the result showed no difference in D3 receptor expression in the amygdala or hippocampus (Fig 10A and 10B); however, there was a significant increase in D3 receptor expression in the nucleus accumbens of female mice (p<0.01, Student’s t-test; Fig 10C and S2 Fig) and no change in D3 receptor expression in nucleus accumbens of male mice (Fig 10D). Together these results suggest that the decrease of D3 receptor expression and loss of D3 receptor signaling function in the amygdala might contribute to the adult anxiety- and depression-related behaviors in male mice that were subjected to preadolescent stress and social isolation. In contrast, an increase in expression of D3 receptor in the nucleus accumbens of female mice subjected to preadolescent stress and social isolation might contribute to depression-related disorders in adulthood.

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