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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 antagonist on preadolescent stress-induced anxiety-related behaviors in adult drd3-EGFP mice.Adult male drd3-EGFP mice were either not stressed (blue, n = 11) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 11). Horizontal locomotor activity (A) and number of center zone entries (B) were measured in an Open Field test in adulthood. Significant reduction in locomotor activity and center zone entries were observed in stressed drd3-EGFP mice (*, p<0.05). Administration of 10 mg/kg SB277011-A (green cross hatch; n = 6) but not saline (pink cross hatch, n = 6) to drd3-EGFP mice ten minutes before each restraint stress episode during preadolescence prevented the reduction of locomotor activity (A) and center zone entries observed in adulthood (B) (**, p<0.001 compared to saline-injected stressed mice and +, p<0.05 compared to non-injected stressed mice). Error bars represents ± SEM.
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pone.0143908.g005: Effect of D3 receptor antagonist on preadolescent stress-induced anxiety-related behaviors in adult drd3-EGFP mice.Adult male drd3-EGFP mice were either not stressed (blue, n = 11) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 11). Horizontal locomotor activity (A) and number of center zone entries (B) were measured in an Open Field test in adulthood. Significant reduction in locomotor activity and center zone entries were observed in stressed drd3-EGFP mice (*, p<0.05). Administration of 10 mg/kg SB277011-A (green cross hatch; n = 6) but not saline (pink cross hatch, n = 6) to drd3-EGFP mice ten minutes before each restraint stress episode during preadolescence prevented the reduction of locomotor activity (A) and center zone entries observed in adulthood (B) (**, p<0.001 compared to saline-injected stressed mice and +, p<0.05 compared to non-injected stressed mice). Error bars represents ± SEM.

Mentions: Consistent with the studies using D3 receptor knock-out mice, the transient reduction in adult locomotor activity and center zone entries in a novel environment was blocked when the preadolescent male 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. 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 transient reduction in locomotor activity during the initial 15 minutes in the novel arena was significantly attenuated in adult male mice that were administered SB277011-A before each restraint stress episode during preadolescence (p<0.001, F3,30 = 14.1, one-way ANOVA, SNK post-hoc test; Fig 5A). Similarly, the transient reduction in center zone entries was significantly blocked in male mice that were administered SB277011-A prior to each restraint stress episode during preadolescence (p = 0.004, F3,30 = 5.15, one-way ANOVA, SNK post-hoc test; Fig 5B).


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

Seo JH, Kuzhikandathil EV - PLoS ONE (2015)

Effect of D3 receptor antagonist on preadolescent stress-induced anxiety-related behaviors in adult drd3-EGFP mice.Adult male drd3-EGFP mice were either not stressed (blue, n = 11) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 11). Horizontal locomotor activity (A) and number of center zone entries (B) were measured in an Open Field test in adulthood. Significant reduction in locomotor activity and center zone entries were observed in stressed drd3-EGFP mice (*, p<0.05). Administration of 10 mg/kg SB277011-A (green cross hatch; n = 6) but not saline (pink cross hatch, n = 6) to drd3-EGFP mice ten minutes before each restraint stress episode during preadolescence prevented the reduction of locomotor activity (A) and center zone entries observed in adulthood (B) (**, p<0.001 compared to saline-injected stressed mice and +, p<0.05 compared to non-injected stressed mice). Error bars represents ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0143908.g005: Effect of D3 receptor antagonist on preadolescent stress-induced anxiety-related behaviors in adult drd3-EGFP mice.Adult male drd3-EGFP mice were either not stressed (blue, n = 11) or subjected to repeated restraint stress and social isolation during preadolescence (red, n = 11). Horizontal locomotor activity (A) and number of center zone entries (B) were measured in an Open Field test in adulthood. Significant reduction in locomotor activity and center zone entries were observed in stressed drd3-EGFP mice (*, p<0.05). Administration of 10 mg/kg SB277011-A (green cross hatch; n = 6) but not saline (pink cross hatch, n = 6) to drd3-EGFP mice ten minutes before each restraint stress episode during preadolescence prevented the reduction of locomotor activity (A) and center zone entries observed in adulthood (B) (**, p<0.001 compared to saline-injected stressed mice and +, p<0.05 compared to non-injected stressed mice). Error bars represents ± SEM.
Mentions: Consistent with the studies using D3 receptor knock-out mice, the transient reduction in adult locomotor activity and center zone entries in a novel environment was blocked when the preadolescent male 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. 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 transient reduction in locomotor activity during the initial 15 minutes in the novel arena was significantly attenuated in adult male mice that were administered SB277011-A before each restraint stress episode during preadolescence (p<0.001, F3,30 = 14.1, one-way ANOVA, SNK post-hoc test; Fig 5A). Similarly, the transient reduction in center zone entries was significantly blocked in male mice that were administered SB277011-A prior to each restraint stress episode during preadolescence (p = 0.004, F3,30 = 5.15, one-way ANOVA, SNK post-hoc test; Fig 5B).

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