Effects Of Repeated Antidepressant Fluoxetine Treatment On Behavior And Brain In Normal Male Sprague-Dawley Rats

Depression is a common global public health problem with an increasing incidence.According to the World Health Organization,depression is one of the leading causes of disability and death worldwide,coming the ninth just behind prolific killers such as heart disease,stroke,and HIV.More than 350 million people are now living with depression,with an increase of more than 18%between 2005 and 2015.At its worst,depression can lead to suicide.It is estimated that close to 800,000 people die of depression-related suicide every year.Abnormalities in brain function and structure contribute to the pathogenesis of depression.Psychological and pharmacological treatments have been developed to cure depression.With the increases of depression diagnosis and antidepressant prescription worldwide,the tendency of antidepressant abuse has emerged,especially among the younger populations.For example,the antidepressant prescriptions to young people increased,on average,41%across the UK,US,Denmark,Germany,and the Netherlands.Due to the lack of psychiatrists in China,there may be misdiagnosis and drug abuse,which leads to more and more atyoical depressive patients taking antidepressants.The research work in this dissertation investigated the effects of a widely used antidepressant,fluoxetine(Flx),on the behaviors and brain in normal male rats.Firstly,the age-specific effects of repeated Flx treatment on normal male SD rats were investigated by magnetic resonance imaging(MRI),behavioral tests and Golgi-Cox staining.It was observed that the Flx-related changes in the adolescent rats were mostly observed in the hippocampus,while those in the adult rats were found mostly in the mPFC.with decreased hippocampal voxel-based morphometry(VBM)signal of gray matter(GM),increased hippocampal neuroplasiticity,enhanced spatial mermory in the adolescent rats,and with decreased VBM signal of gray matter in the prefrontal cortex in the adult rats.Secondly,the short-term and long-term effects of repeated Flx treatment on adult male SD rats were investigated.The VBM data revealed significant GM atrophy and in vivo~1H-MRS measurements revealed significantly reduced concentration of the glial-related metabolites in the mPFC,which were thought to be short-term effects.The GM atrophy and decreased expression of neurovascular-related molecular in prefrontal cortex,and WM atrophy in callosum were thought to be long-term effects.Thirdly,the long-lasting effects of repeated Flx treatment on the function and structure of rat prefrontal cortex were investigated with behavioral,Golgi-Cox staining,Western blotting,and immunohistochemical assessments.The results demonstrated that repeated Flx treatment induced significant neurotrophic effects on the medial prefrontal cortex(mPFC)of normal adult rats.Such changes were shown to be long-lasting and subregion-specific,persisting at least up to 20 days after the last Flx dose and being more prominent in the prelimbic cortex(PrL)than in the infralimbic cortex(IL).Furthermore,the long-lasting neurotrophic effects of repeated Flx treatment on the adult mPFC were shown to be associated with upregulation of BDNF/TrkB signaling and decreased parvalbumin(PV)-related neurotransmission.Behaviorally the Flx-treated rats showed significantly increased willingness to explore novel environments.In summary,the work in this dissertation assessed the effects of repeated antidepressant Flx treatment on the brain and behaviors of normal male rats.It was demonstrated that repeated Flx treatment induced age-and region-dependent effects,included both short-and long-term effects.And the long-term effects in the mPFC were neurotrophic effects.These findings highlight the need to better undertstand the consequences of antidepressant abuse in normal population.