Adult motivation deficits produced by early developmental fluoxetine exposure are rescued by nucleus accumbens mu opioid receptor antagonism

Adult mice exposed to early developmental fluoxetine show impaired goal-directed effort that is rescued by nucleus accumbens mu opioid receptor antagonism, but only in fluoxetine-exposed animals.

• Why it matters: Reward-seeking deficits linked to depression are poorly managed by frontline SSRIs, motivating alternative mechanisms that target motivational symptoms rather than serotonin alone.
• What they did: In a murine model of early developmental fluoxetine exposure, chronic adult treatment with SSRIs or tianeptine did not improve goal-directed effort, whereas mu opioid receptor antagonism with methocinnamox did; effects were recapitulated by nucleus accumbens MOR knockdown.
• The result: Nucleus accumbens MOR antagonism rescues adult motivation deficits specifically after early-life fluoxetine exposure, identifying a developmental window where elevated serotonin signaling shapes adult NAc MOR-dependent motivation.