Early deprivation leads to long-term reductions in motivation for reward and 5-HT1A binding and both effects are reversed by fluoxetine

Early life stress is a risk factor in aetiology of depression. In rats, early life stress can lead to pro-depressive biomarkers in adulthood. The present study in male Wistar rats investigated the effects of early life deprivation and fluoxetine on motivation for reward, activity in the forced swim test, and brain monoamine receptors, in adulthood. P1-14 pups were isolated for 4 h/day (early deprivation, ED) or were handled for 1 min (CON). They were weaned at PND21 and left undisturbed until 4-6 months old. The ED and CON groups were halved to receive either vehicle or fluoxetine (FLX, 10 mg/kg, 31 days). Thus, four treatment groups were studied: CON-VEH, CON-FLX, ED-VEH and ED-FLX, n = 8 each. On a progressive ratio schedule, ED-VEH animals showed significantly reduced motivation to obtain sucrose versus CON-VEH, and this reward-motivation deficit was reversed by FLX. Activity in the forced swim test was unaffected by ED and increased by FLX. Quantitative autoradiography was used to determine 5-HT1A and 5-HT2C receptor binding with [O-methyl-³H]WAY 100635 and [³H]mesulergine (added spiperone and 8-OH-DPAT), respectively. In ED-VEH versus CON-VEH, 5-HT1A receptor binding was significantly reduced in anterior cingulate, motor cortex, ventral hippocampal CA1 and dorsal raphé; this was reversed by chronic FLX. Concomitant ED-dependent reductions observed in 5-HT2C (motor and frontal cortices, ventral CA1 and dorsal raphé) and D2 (dorsolateral striatum and accumbens) binding were not reversed by FLX. Because chronic FLX treatment reversed the ED-induced behavioural and 5-HT1A binding deficits, the 5-HT1A receptor is implicated as a selective therapeutic target.