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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 D3 receptor antagonism on preadolescent stress-induced depression-related behaviors in adult mice.Administration of 10 mg/kg SB277011-A (n = 6) but not saline (n = 6) to male drd3-EGFP mice ten minutes before each restraint stress episode during preadolescence prevented the reduction in latency to immobility (A) and increase in total immobility time (B) in adulthood (**, p<0.001 compared to saline-injected stressed mice and non-injected stressed mice). Significant differences were also observed between non-stressed mice and saline-injected stressed mice (#, p<0.05). Error bars represents ± SEM.
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pone.0143908.g008: Effect of D3 receptor antagonism on preadolescent stress-induced depression-related behaviors in adult mice.Administration of 10 mg/kg SB277011-A (n = 6) but not saline (n = 6) to male drd3-EGFP mice ten minutes before each restraint stress episode during preadolescence prevented the reduction in latency to immobility (A) and increase in total immobility time (B) in adulthood (**, p<0.001 compared to saline-injected stressed mice and non-injected stressed mice). Significant differences were also observed between non-stressed mice and saline-injected stressed mice (#, p<0.05). Error bars represents ± SEM.

Mentions: The depression-related behaviors observed in the adult mice that were subjected to repetitive restraint stress during preadolescence and social isolation were prevented if the preadolescent drd3-EGFP mice were systemically administered 10 mg/kg SB277011-A, a D3 receptor-selective antagonist, 10 minutes before each restraint stress episode during the P35-P39 preadolescent period (Fig 8A and 8B). Note that these antagonist-injected mice were subjected to both restraint stress and subsequent social isolation as in the previous experiments. In addition, administration of the same dose of SB277011-A (10 mg/kg) to naïve drd3-EGFP mice did not significantly affect basal locomotor activity (S1 Fig). The decrease in latency to immobility, in adulthood, was significantly attenuated in mice that were administered SB277011-A before each preadolescent restraint stress episode (p = 0.01, q = 4.4, one-way ANOVA, post-hoc SNK test; Fig 8A). Similarly, the increase in total immobility time, in adulthood, was significantly reduced in mice that were administered SB277011-A prior to each restraint stress episode during preadolescence (p = 0.006, q = 4.76, one-way ANOVA, post-hoc SNK test; Fig 8B). These results suggest that the dopamine D3 receptor plays a central role in the etiology of adult depression-related disorders that are caused by preadolescent stress and social isolation.


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

Seo JH, Kuzhikandathil EV - PLoS ONE (2015)

Effect of D3 receptor antagonism on preadolescent stress-induced depression-related behaviors in adult mice.Administration of 10 mg/kg SB277011-A (n = 6) but not saline (n = 6) to male drd3-EGFP mice ten minutes before each restraint stress episode during preadolescence prevented the reduction in latency to immobility (A) and increase in total immobility time (B) in adulthood (**, p<0.001 compared to saline-injected stressed mice and non-injected stressed mice). Significant differences were also observed between non-stressed mice and saline-injected stressed mice (#, p<0.05). Error bars represents ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664486&req=5

pone.0143908.g008: Effect of D3 receptor antagonism on preadolescent stress-induced depression-related behaviors in adult mice.Administration of 10 mg/kg SB277011-A (n = 6) but not saline (n = 6) to male drd3-EGFP mice ten minutes before each restraint stress episode during preadolescence prevented the reduction in latency to immobility (A) and increase in total immobility time (B) in adulthood (**, p<0.001 compared to saline-injected stressed mice and non-injected stressed mice). Significant differences were also observed between non-stressed mice and saline-injected stressed mice (#, p<0.05). Error bars represents ± SEM.
Mentions: The depression-related behaviors observed in the adult mice that were subjected to repetitive restraint stress during preadolescence and social isolation were prevented if the preadolescent drd3-EGFP mice were systemically administered 10 mg/kg SB277011-A, a D3 receptor-selective antagonist, 10 minutes before each restraint stress episode during the P35-P39 preadolescent period (Fig 8A and 8B). Note that these antagonist-injected mice were subjected to both restraint stress and subsequent social isolation as in the previous experiments. In addition, administration of the same dose of SB277011-A (10 mg/kg) to naïve drd3-EGFP mice did not significantly affect basal locomotor activity (S1 Fig). The decrease in latency to immobility, in adulthood, was significantly attenuated in mice that were administered SB277011-A before each preadolescent restraint stress episode (p = 0.01, q = 4.4, one-way ANOVA, post-hoc SNK test; Fig 8A). Similarly, the increase in total immobility time, in adulthood, was significantly reduced in mice that were administered SB277011-A prior to each restraint stress episode during preadolescence (p = 0.006, q = 4.76, one-way ANOVA, post-hoc SNK test; Fig 8B). These results suggest that the dopamine D3 receptor plays a central role in the etiology of adult depression-related disorders that are caused by preadolescent stress and social isolation.

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