Background: Both genes and environment play a role in depressive disorders. While a dysregulation of the monoaminergic systems may be sufficient to cause depression, a growing body of data indicates that other endogenous compounds, such as neuropeptides, as well as hippocampal cell loss/neurogenesis may be important in pathophysiology and treatment of depression. With regard to treatment, it is not clear whether early intervention could alleviate or prevent the disorder. Consequently, we studied neuropeptides in I. CSF from depressed inpatients before and after citalopram treatment, and II. brains of animal models: (i) genetic - the Flinders Sensitive Line (FSL) rat and their controls, the FRL line, (ii) environmental - early maternal separation that mimics early life trauma in humans, experiences that predict adult life psychopathology. Method: In human studies, CSF was collected before and after 5 weeks of citalopram treatment. In animals, early life maternal separation was superimposed on the FSL and FRL rats and behavior studied when the animals reached adulthood, and brain neurochemistry and cell proliferation post-mortem. On postnatal days (PND) 2−14, FSL and FRL pups were maternally separated. Escitalopram or vehicle in food were started on PND 44. Porsolt swim test was done on PND 64−65. Results: In patients, CRH was decreased and NPY increased following successful citalopram treatment. Strong correlations between CRH decrease, NPY increase and clinical outcome were found. In animals, baseline FSL-FRL differences were found in the Porsolt swim test and in brain neuropeptides, in particular NPY and CGRP in selected brain regions. Cell proliferation was also affected. Moreover, maternal separation and escitalopram also differentiated between the strains. Conclusions: Both genes and environment play a role in depression but the consequences of early life events are more deleterious in genetically vulnerable individuals. NPY and CRH as well as cell proliferation changes appear to constitute biological correlates of depression and may be markers of treatment. Lastly, results from our animal studies raise a question whether early drug intervention should be explored as a potential strategy to alleviate adult life psychopathology.

Although the etiology of major psychiatric disorders has not been elucidated, accumulating evidence indicates that both genetic and early environmental factors play a role.We have previously demonstrated behavioral and neurochemical changes both in non-manipulated genetic rat models of depression, such as Flinders Sensitive Line (FSL) and Fawn Hooded (FH), and in normal rats following maternal separation (MS). The aim of the present study was to extend this work by exploring whether neurotensin (NT), a peptide implicated in several psychiatric disorders, is altered in a new animal model based on gene – environment interactions.More specifically, we used the FSL rats as a genetic model of depression and the Flinders Resistant Line (FRL) as controls and subjected them to MS. Pups randomly assigned to the MS procedure were separated from the dam as a litter for 180 min daily between postnatal day 2 to 14. On postnatal day 90, rats were weighed and sacrificed by a two second high energy focused microwave irradiation and several brain regions were obtained by micropuncture. Neurotensin-like immunoreactivity (NT-LI) was measured by radioimmunoassay (RIA).The results showed that the FSL rats compared to the FRL rats have higher baseline NT-LI concentrations in the temporal cortex and periaqueductal gray and a markedly different response to maternal separation. The only observed change following maternal separation in the FRL rats was an NT-LI increase in the periaqueductal gray. In contrast, in the FSL significant increases were found in the nucleus accumbens, hippocampus, and entorhinal cortex and a decrease was seen in the temporal cortex after MS.The present study revealed baseline regional differences in NT-LI concentrations between the FSL and FRL strains and demonstrated that early MD differentially affects the two strains. The relevance of these alterations for depression as well as possible mechanisms underlying this gene-environment interaction are discussed.