Modelling early life exposure to antidepressants in rats: Developmental, behavioural and neurochemical aspects
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Depression during pregnancy and the postpartum period has been associated with deleterious consequences such as preterm birth, low birth weight and less optimal scores on neonatal reflexes and behaviour. Pharmacological intervention is often advised; however, this in itself has been associated with these outcomes, thus creating a treatment dilemma. It is ethically and logistically impossible to carry out long-term controlled studies into later effects of early life exposure to antidepressants in a clinical population; animal models provide an alternative. The present work aimed to investigate the developmental, behavioural and neurochemical effects of exposure to the antidepressants amitriptyline and fluoxetine in the rat following a variety of exposures: 1) prenatal exposure via maternal administration; 2) prenatal and/or postnatal exposure via maternal administration and 3) direct postnatal administration; direct administration of clomipramine was also investigated as behavioural and neurochemical changes have been seen previously with this drug. Administration of the drugs during gestation was not found to result in maternal toxicity, as no decreases in body weight were observed. Birth weight was found to be decreased following exposure to both drugs via maternal administration and there were sporadic alterations in body weight throughout the neonatal period. Direct drug administration decreased body weight during the dosing period, but these decreases did not endure once drug administration ceased. All drugs had effects on anxiety-like behaviour in the elevated plus maze; however these effects were dependent upon duration of exposure and age of testing. There were no effects of drug exposure in the forced swim test, a model of ¿behavioural despair¿ or on spatial learning and memory in the Morris water maze. There were transient changes in monoamine levels following prenatal exposure to amitriptyline and fluoxetine, but no effects of direct administration of any drug were seen on this parameter or on the number of tryptophan hydroxylase cells in the dorsal raphe nucleus. A number of sex effects were seen, with females exhibiting a delay in acquisition of the surface righting reflex, increased locomotor activity in the open field during adulthood and decreased immobility in the forced swim test. This research has shown that early exposure to the antidepressants amitriptyline and fluoxetine results in transient changes in body weight, anxiety-like behaviour and monoamine levels. It is recommended that the behavioural profile presented herein be expanded upon in order to better determine the extent of behavioural teratogenicity of these drugs.
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