Epidemiological studies showed that the negative life events in adolescence increased the individual susceptibility to mood disorders, such as depression and anxiety. However, the developmental neurobiological mechanisms by which adolescent stress leads to psychopathology remain unknown. In this study, we examined the long-term effects of different stress paradigms (social isolation versus chronic mild stress) delivered at different development stage (adolescence versus adulthood) on emotional behaviors and monoamines in prefrontal cortex and subcortical limbic,areas, as well as the treatment efficacy of antidepressants. Depression-like behaviors were detected by sucrose preference test (an index of anhedonia), open field (OF) test and forced swimming test (FST), while anxiety-like behaviors were tested in elevated plus-maze (EPM). A high performance liquid chromatographic method was used to determine the level of monoamines and their metabolites in prefrontal, hippocampus, amygdala and striatum. The results were as follows: 1. Chronic mild stress in adolescence (PND28-41) had no effects on sucrose preferences and locomotion activity of adult rats (> PND62). But previously stressed rats exhibited an increased immobility/despair behavior and decreased climbing behavior in FST. In addition, the adult rats suffering stress during adolescence showed increased anxiety-like behavior in EPM. 2. Chronic mild stress in adolescence affected adult monoamines and metablites levels in several limbic regions, causing increased 5-HT turnover rate (5-HIAA/5-HT) in striatum and DA content in amygdale, and decreased 5-HIAA/5-HT in hippocampus.Moreover, the number of climbing behavior and immobility behavior in FST respectively had a negative and positive correlation with 5-HIAA/5-HT in striatum. 3. Both 5 - HT reuptake inhibitors fluoxetine and dopamine reuptake inhibitor bupropion can reduce immobility behavior, and increased swimming behavior and climbing behavior in FST respectively. However, flunexine exerted greater behavioral effects in FST in controls than stressed rats. In addition, fluoxetine can reverse the increase of 5-HIAA/5-HT in the striatum induced by adolescent stress, while bupropion can reverse the increase of DA level in amygdale induced by adolescent stress. In summary, chronic mild stress during adolescentce did not affect the instinct preference for sucrose of adult rats, but impaired behaviors implicated in motivation and stress coping. Rats exposure to adolescent chronic mild stress developed more significant despair behaviors after acute severe stress in adulthood. In addition, the long-term effects of chronic mild stress during adolescence on behavior draw a parallel with changes in 5-HT turnover rate in striatum and DA content in amygdale, all of that can be reversed by antidepressant fluoxetine and bupropion treatment respectively. These results suggested that the “adolescent chronic mild stress” model might be relevant to reported predisposition to develop depressive behaviors following stress in adulthood.
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