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 tress can lead to prodepressive 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 I 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 (FIX, 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 CONVEH, and this reward-motivation deficit was reversed by FIX. 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-H-3]WAY 100635 and [H-3]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 raphe: this was reversed by chronic FIX. Concomitant ED-dependent reductions observed in 5-HT2C (motor and frontal cortices, ventral CA1 and dorsal raphe) and D2 (dorsolateral striatum and accumbens) binding were not reversed by FIX. Because chronic FIX treatment reversed the ED-induced behavioural and 5-HT1A binding deficits, the 5-HT1A receptor is implicated as a selective therapeutic target. (C) 2008 Elsevier Ltd. All rights reserved.