Prozac Exposure During Adolescence Alters Responses to Aversive Stimuli in Adulthood

RM 215-218

The mechanisms underlying the enduring neurobiological consequences of antidepressant exposure during adolescence are poorly understood. Thus, we examined the long-term effects of exposure to fluoxetine (FLX), also known as Prozac, during adolescence on behavioral reactivity to the tail suspension test (TST) - a behavioral measure commonly used to screen for antidepressant efficacy in rodent models of depression. Specifically, we administered FLX (20 mg/kg) to adolescent c57BL/6 male mice (postnatal days 35-49), and assessed their reactivity to the TST, 21 days after treatment (i.e. adulthood). Repeated FLX exposure during adolescence resulted in decreased time spent immobile, when compared to saline (placebo) pretreated animals, in adulthood (i.e. an enduring antidepressant-like behavior). To characterize the neurobiological mechanisms that underlies this behavioral phenotype, we examined the role of extracellular signal-regulated kinase (ERK), a signaling molecule that has been previously implicated in mood regulation, within the ventral tegmental area (VTA) of the midbrain. To do this, we used a virus-mediated gene transfer approach to experimentally manipulate ERK expression within the VTA of adult mice (postnatal day 70) pretreated with either saline of FLX during adolescence. Virus-mediated upregulation of ERK activity within the VTA reversed the enduring effects induced by juvenile FLX pretreatment, suggesting that FLX exposure during adolescence modulates responses to aversive stimuli in adulthood via long-lasting adaptations in ERK signaling within the VTA.