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-null 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 null 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.
Highlights
The transition from adolescence to adulthood is associated with many behavioral changes
Male drd3-enhanced green fluorescent protein (EGFP) mice that were subjected to preadolescent repetitive restraint stress followed by social isolation exhibited, in adulthood, a significant reduction in locomotor activity in a novel environment (p = 0.021, F1,242 = 6.166, two-way repeated measure ANOVA; Fig 1A) wherein, post-hoc Student Neuman Keuls (SNK) test revealed significant difference between the non-stressed and stressed mice only at the 10 min (q = 4.274, p = 0.004), 15 min (q = 4.667, p = 0.002) and 20 min (q = 3.185, p = 0.028) time points
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 locomotor activity in a novel environment (p = 0.144, F1,165 = 2.380, two-way repeated measure ANOVA; Fig 1C) and, post-hoc SNK test did not reveal significant difference between the non-stressed and stressed mice at any time points
Summary
The transition from adolescence to adulthood is associated with many behavioral changes. In humans and rodents repeated or chronic stress during preadolescence has long-lasting effects and result in development of behavioral disorders as adults [1,2,3,4,5,6,7,8,9]. In a Center for Disease Control study published in 2008, a survey of 17,000 adults revealed that ~64% had experienced one or more adverse childhood experience [3]. Preadolescent Stress-Induced Disorders and D3 Receptor Dysfunction correlated to attempted suicides, substance abuse and depressive disorders in adulthood [1,2,3,4,5,6,7,8,9]. Molecular mechanisms by which adverse childhood experiences cause psychiatric disorders in adults are not well understood
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