433 Uncovering an unexpected therapeutic target for motivational deficits following early-life exposure to SSRIs

Objectives/Goals: Motivational deficits are associated with depression and poorly treated by current therapeutics. We sought to identify more effective therapeutics for these deficits using a mouse model of early-life exposure to SSRIs, a developmental risk factor identified for depression in humans. Methods/Study Population: Mice were administered the SSRI, fluoxetine (FLX), or a vehicle control from postnatal day P2-P11, a window that mimics brain development occurring during the third trimester in a human pregnancy. Motivation and hedonic perception were assessed in adulthood using the progressive ratio and lickometer tasks, respectively. Behavioral testing was repeated after chronic adult administration of either an SSRI (fluoxetine), an atypical antidepressant and mu-opioid receptor agonist (tianeptine), or a mu-opioid receptor antagonist (methocinnamox). Results/Anticipated Results: Mice administered FLX in early-life showed motivational deficits in the progressive ratio task, while hedonic perception, as measured by the lickometer task, remained intact. Chronic administration of FLX in adulthood did not improve motivational deficits and did not alter hedonic perception. Chronic administration of tianeptine (TIA) slightly improved motivational behavior without altering hedonic perception. In contrast, chronic administration of the mu opioid antagonist methocinnamox (MCAM) markedly improved motivational deficits in mice, even while blunting hedonic perception. The ability of MCAM to enhance motivation was selective to early-FLX exposed mice Discussion/Significance of Impact: Our results reveal that unexpectedly opioid receptor antagonism is effective at improving motivation in mice exposed to SSRIs in early life. This suggests potential novel treatment approaches in individuals with motivational impairments and a history of in utero exposure to SSRIs.