Juvenile Injection Fluoxetine Induced Murine Model Of Adult Depression

ObjectiveNeonatal exposure to antidepressants, including selective serotonin reuptake inhibitors (SSRI) such as citalopram and clomipramine could Induce the adult behavioral abnormalities in rodents. However, the inconsistent evidences make this paradigm far from a valid depression amimal model. Our study investigated the depression paradigm of neonatal exposure to fluoxetine (FLU) in adult mice and the effect of antidepressant treatments, thus adding a proof to this paradigm as an endogenous depression animal model and providing evidence for elucidating the mechanism of antidepressants. We examined the behavioral abnormalities and the level of monoamine neurotransmitters in adult mice neonatally exposed to fluoxetine. Meanwhile, we detected the effects of adult antidepressant treatment with fluoxetine or desipramine.MethodsWe examined the behavioral and neurotransmitter effects on mature mice with early life exposure to fluoxetine through three aspects:(1) The neonatal ICR mice were randomly injected intraperitoneally (i.p.) with sanline (NS, control group/Nor) or FLU (postnatal fluoxetine treatment/PNF), at a dose of 10 mg/kg and in a volume of 10ml/kg one daily during postnatal day d4 until d21. the behavioral tests were started at the age of 6 to 7 weeks old at two days interval. We employed open-field test (OPT), tail suspension test (TST), forced swimming test (FST), elevated plus-maze (EPM), novelty-suppressed feeding test (NSFT) and light-dark transition to investigate behavioral disturbances in adults with neonatal exposure to fluoxetine.(2) During the age of 9 to 10w, litters of neonatal FLU exposure group were randomly assigned to four groups: water-drinking (PNF+W) and i.g. FLU (PNF+FLU, 10 mg/kg), DMI (PNF+DMI, 15 mg/kg) and haloperidol (PNF+HAL, 0.1 mg/kg), a robust antipsychotic, in a volume of 10 ml/kg, once daily. Neonates injected with saline were administered water (NS+W) in a volume of 10ml/kg, i.g.. Each group contained 13-15 pups, and the treatment continued for 21 days prior to the behavioral testing started and through all behavioral sessions 1h before until sacrifice. (3) We employed high performance liquid chromatography with electrochemical detector (HPLC-ECD) to estimate the effect of neonatal exposure to FLU and antidepressant treatment in adults on levels of monoamine neurotrasmitters and their metabolites in hippocampus and prefrontal cortex .Results1. Neonatal exposure to FLU Induced behavioral disturbances in adult miceNeonatal exposure to FLU significantly increased the immobility time in TST and FST while decreased the parameters in open-field test in adults, Indicating of behavioral despair and reduced exploratory behavior. And also, the light-dark transitions were robustly decreased, while the latency to novelty-suppressed feeding was prolonged, suggesting that there was anxiety-like behavior changes in adult mice.2. chronic antidepressant treatment with FLU and DMI of adult micechronic FLU treatment drastically increased the parameters in open-field test of neonatal FLU exposure mice, Indicating that chronic FLU administration increased exploratory behavior. Meanwhile, significantly increased the immobility time in TST of neonatal FLU exposure mice, reversing the"behavioral despair". Also, dramatically increased the light-dark transitions, suggesting that the anxiety-like behavior was restored by chronic FLU treatment too. Chronic administration with DMI did not reveal any changes in the behavioral tests.3. the level of monoamine neurotransmitters and their metabolites in hippocampus and prefrontal cortexNeonatal administration of FLU resulted in decreased level of norepinephrine and serotonergic neurotransmission in the prefrontal cortex of adult mice. Chronic FLU treatment enhanced serotonergic neurotransmission through raising the content of 5-HT and reducing 5-HIAA level as well as 5-HT turnover rate (5- HIAA/5-HT %). However, chronic FLU treatment had no significant effects on the content of NE. In hippocampus, levels of monoamine neurotransmitters were not changed. It suggested that enhanced serotonergic neurotransmission was important to the antidepressant effect of chronic FLU treatment in this paradigm. Meanwhile, the disturbance of neonatal FLU exposure to adult neurotransmitter contents differed between brain tissues. levels of monoamine neurotransmitters in both hippocampus and prefrontal cortex were not affected neither by chronic administrations of DMI nor HAL.ConclusionNeonatal FLU exposure resulted in depression and anxiety-like behaviors which persisted into adulthood and reduced levels of monoamine neurotransmitters in prefrontal cortex of ICR mice. Chronic FLU treatment reversed the maladaptive behaviors and increased the contents of monoamine neurotransmitters in prefrontal cortex. No such reversal was observed in handled, saline treated mice. The behavioral alterations were accompanied by changes in monoamine neurotransmitter level. Our experiments show that behavioral and the level of monoamine transmitter Induced by early postnatal fluoxetine administration are reversed by chronic fluoxetine treatment of adult mice to control levels. The present data support the hypothesis that some of the lasting behavioral abnormalities Induced by early antidepressant exposure are sensitive to clinically relevant antidepressant treatments, thus adding a proof to this paradigm as an endogenous depression animal model and drawing light on elucidating the mechanism of antidepressants.