Fluoxetine Exposure during Adolescence Alters Responses to Aversive Stimuli in Adulthood

Abstract

The mechanisms underlying the enduring neurobiological consequences of antidepressant exposure during adolescence are poorly understood. Here, we assessed the long-term effects of exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, during adolescence on behavioral reactivity to emotion-eliciting stimuli. We administered FLX (10 mg/kg, bi-daily, for 15 d) to male adolescent [postnatal day 35 (P35) to P49] C57BL/6 mice. Three weeks after treatment (P70), reactivity to aversive stimuli (i.e., social defeat stress, forced swimming, and elevated plus maze) was assessed. We also examined the effects of FLX on the expression of extracellular signalregulated kinase (ERK) 1/2-related signaling within the ventral tegmental area (VTA) of adolescent mice and Sprague Dawley rats. Adolescent FLX exposure suppressed depression-like behavior, as measured by the social interaction and forced swim tests, while enhancing anxiety-like responses in the elevated plus maze in adulthood. This complex behavioral profile was accompanied by decreases in ERK2 mRNA and protein phosphorylation within the VTA, while stress alone resulted in opposite neurobiological effects. Pharmacological (U0126) inhibition, as well as virus-mediated downregulation of ERK within the VTA mimicked the antidepressant-like profile observed after juvenile FLX treatment. Conversely, overexpression of ERK2 induced a depressive-like response, regardless of FLX pre-exposure. These findings demonstrate that exposure to FLX during adolescence modulates responsiveness to emotion-eliciting stimuli in adulthood, at least partially, via long-lasting adaptations in ERK-related signaling within the VTA. Our results further delineate the role ERK plays in regulating mood-related behaviors across the lifespan.

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…Such tight confinement of this sensitive period, however, does not persist when comparing between species. For example, although in mice, PA SSRI exposure lacks persistent consequences on fear-, anxiety-, or stress-related behaviors (Norcross et al, 2008;Yu et al, 2014), rats exhibit increases in anxiety-like behavior following P25-P46, P35-P49, or P67-P88 5-HTT blockade (Iniguez et al, 2010(Iniguez et al, , 2014Karpova et al, 2009). Likewise, although in mice, 5-HTT blockade between P2 and P11 impairs cognitive behavior (Rebello et al, 2014), pharmacological perturbations that enhance levels of 5-HT from P11 to P20 but not from P1 to P10 result in dose-related impairments of sequential learning and spatial learning and memory in rats (Broening et al, 2001;Morford et al, 2002).…”

“…Although clomipramine or SSRI exposure in rats from P8 to P21 causes enhanced immobility in the forced swim test (Hansen et al, 1997;Vogel et al, 1990); PA (P35-P49), but not adult (P65-P79), fluoxetine (FLX) exposure reduces floating (Iniguez et al, 2010). In mice, P2-P11 FLX exposure increases forced swim test immobility (Rebello et al, 2014), whereas P4-P21 or P35-P49 FLX exposure reduces floating (Iniguez et al, 2014;Karpova et al, 2009).…”

Voluntary exercise and increased food intake after mild chronic stress improve social avoidance behavior in mice

“…This model is also called "the resident-intruder paradigm" because an "intruder" (experimental) animal is placed in the cage of a "resident" (aggressor) animal. Rodents exposed to SDS show a variety of behavioral changes, including social avoidance [12,13], which has been shown to improve with the administration of anti-depression medication [14,15,16,17]. Therefore, social avoidance induced by SDS is used as a measure of depressive-like behavior and sociality.…”

Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice

“…In addition, adolescent (P12–21; P21–49; P22–41) or adult (P56–P84) fluoxetine administration did not lead to long-term changes in anxiety-like or fear extinction behaviors in wild-type mice (11, 12). On the other hand, rats receiving fluoxetine P25–46, P35–49, or P67–88 spend significantly less time in the open arm of the elevated plus maze at 1–3 weeks following drug cessation (14, 15, 60), suggesting species-specific effects of SERT blockade across development (61). The reported discrepancies could be due to a number of methodological factors such as dose and delivery route of fluoxetine, duration of drug exposure.…”

“…Interestingly, in primates, no effects were observed on fear-related or social behaviors (8). In rodents early life fluoxetine did not change anxiety-like or fear extinction behaviors in adulthood (11–13), however, conflicting reports exist (14, 15). Importantly, all preclinical studies were performed in wild-type animals that did not exhibit elevated depressive or anxiety-like phenotypes, for which SSRIs are indicated in human populations.…”