Windows of vulnerability: maternal separation, age, and fluoxetine on adolescent depressive-like behavior in rats

Abstract

Early exposure to stressful life events plays a significant role in adolescent depression. Clinical studies have identified a number of factors that increase the risk of depression, including sex of the subject, duration of the stressor, and genetic polymorphisms that elevate serotonin levels. In this study we used the maternal separation (MS) model to investigate to what extent these factors interacted during development to manifest in depressive-like behavior in male and female rats. The triadic model of learned helplessness parses depressive-like behavior into aspects of controllable, uncontrollable, and motivational behaviors. This model was used to investigate how the timing of MS between the ages of postnatal day (P) 2-9 and P9-16 interacted with either simultaneous vehicle (saline; 1ml/kg; i.p.) or fluoxetine (10mg/kg) exposure, which was used to enhance serotonin levels; these experiments also compared the effect of a vehicle injection during these developmental periods to a no injection control. Vehicle injections alone increased helplessness in the controllable condition in male rats when injected between P9-16 only, and did not interact further with MS. MS at both ages decreased controllability in male adolescents; females demonstrated an increase in controllability after MS. Elevated serotonin at P2-9 increased escape latencies in male and female control and MS subjects. Fluoxetine exposure at P9-16 increased helplessness in controls. Fluoxetine decreased helplessness in MS males independent of age, but increases helplessness in MS females. This study highlights the importance of age of MS (MS between P2-9 increases helplessness in males more than females), the duration of the stressor (previous results show females are effected by longer MS [P2-20], but not shorter [this study]), and that elevated serotonin increases escape latencies to a greater extent in females.

Keywords: ES; IS; LH; MS; NS; P; abuse; adolescence; depression; escapable shock; fluoxetine; inescapable shock; learned helplessness; maternal separation; no shock; postnatal day; stress.

Fig. 1

The experimental design. Animals were assigned to a No injection condition, a control condition (CON) or maternal separation (MS) condition. They were then treated with saline vehicle or fluoxetine (with the exception of the No injection condition) and tested for depressive behavior under escapable (ES), inescapable (IS) or a no shock (NS) condition. The number of subjects is shown in parentheses.

Fig. 2

Weight gain across nine days of MS (or control conditions) is shown across Sex and Drug. **P < 0.05 indicating a significant difference between MS and Control. Means only are presented for clarity.

Fig. 3

The effect of injection on depressive-like behavior. In both males (left) and females (right), the timing of a saline injection at either P2–9 in Control subjects (CON2) or P9–16 (CON9) had differential effects on behavior. *P < 0.05; showing comparisons between the ES group specifically; ^#P < 0.05 indicates a difference between CON2 IS and the other IS groups; **P < 0.05 indicates that the CON9 group, independent of triad condition, differed from the No injection and the CON2 groups. Means ± SEM are presented.

Fig. 4

The effect of vehicle or fluoxetine on MS2 and MS9 on adolescent learned helplessness in males. Escape failures (top) or escape latencies (bottom) following simultaneous exposure to vehicle or 10 mg/kg fluoxetine in Controls or during the MS paradigm. *P < 0.05 within the ES condition alone. Means ± SEM are presented.

Fig. 5

The effect of vehicle or fluoxetine on MS2 and MS9 on adolescent learned helplessness in females. Escape failures (top) or escape latencies (bottom) following simultaneous exposure to vehicle or 10 mg/kg fluoxetine in Controls or during the MS paradigm. Means ± SEM are presented.