Influência da exposição neonatal à fluoxetina sobre o comportamento e expressão neuroquímica de parvalbumina em ratos Wistar machos e fêmeas, juvenis e adultos

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat depression, anxiety and other disorders. The developmental exposure to selective serotonin reuptake inhibitors (SSRIs) results in persistent behavioural impairment into adulthood. In this way, serotonergic overexpression in early life may lead to structural and functional changes in brain circuits that control cognitive and emotional behaviour. Here, we addressed the question of how postnatal (PND7PND21) exposure to fluoxetine affects memory, anxietyand depressionlike behaviours, as well as neurochemical markers of interneurons and serotonergic cells in brain areas related to these behaviours in juvenile (PND45) and adult (PND90) female and male rats. In a first stage, we analysed both female and male rat’s performances in several behavioural tasks and investigated the expression of serotonin (5HT) in the dorsal and median nucleus of raphe, and parvalbumin (PV) in PFCm and hippocampus at PND45. We found that earlylife exposure to fluoxetine increased anxietyand depressionlike behaviours (more in female compared to male animals), and induced a working memory impairment only in the juvenile male. Afterwards, we performed behavioural and neurochemical analysis of male and female adult rats (PND90), where we found that fluoxetine affects only anxietyrelated male behaviour. Also, the memory impairment (more in male than female) and depressivelike profile (both sexes) remained in adult age. Moreover, the exposure to fluoxetine affect PV immunoreactivity in the hippocampus in any sex at PND45 and PND90; however, adult animals appear to recover neurochemical deficits observed at the juvenile age. The results revealed developmental fluoxetine effects on juvenile behaviour that can have implications for affective disorders and mnemonic processes. These results revealed persistent changes a sex and agemanner related to developmental exposure to fluoxetine, where serotonergic modulation induce differential profile of anxietyand depressionlike behaviour and mnemonic impairment on female and male rats at juvenile and adult age. Also, suggest a sexdependent compensatory mechanism, which it is possibly related to serotonergic sinalisation. Circuits may involve subcortical and cortical information processing, including subcortical limbic and possible (pre)frontal areas. Thus, our findings suggest that serotonergic modulation during critical periods of SNC development may alter the organisation of excitatoryinhibitory circuit and induce behavioural changes, which may have repercussions for the onset of neuropsychiatric disorders.