Gene–environment interaction affects substance P and neurokinin A in the entorhinal cortex and periaqueductal grey in a genetic animal model of depression: implications for the pathophysiology of depression

Abstract

Evidence implies a role for corticotropin-releasing hormone (CRH) and tachykinins, e.g. substance P (SP) and neurokinin A (NKA) in the pathophysiology of depression. We have previously shown that SP- and NKA-like immunoreactivity (-LI) concentrations were altered in the frontal cortex and striatum of the congenitally 'depressed' Flinders Sensitive Line (FSL) compared to the Flinders Resistant Line (FRL) control rats. It is also known that environmental stress may affect brain levels of tachykinins. In view of these results we decided to superimpose maternal deprivation, an early life environmental stressor, onto the genetically predisposed 'depressed' FSL rats and the FRL control rats and use this paradigm as a model of gene-environment interaction. The adult animals were sacrificed, adrenal glands and brains dissected out and SP-, NKA- and CRH-LI levels were determined in ten discrete brain regions. Maternal deprivation led to a marked increase in SP-LI and NKA-LI levels in the periaqueductal grey (PAG) and entorhinal cortex of the 'depressed' FSL strain while it had no significant effect in the FRL controls. Furthermore, specific strain differences in peptide-LI content were confirmed. No difference was found in relative adrenal gland weight, which is consistent with the finding that CRH-LI levels in the hypothalamus were similar across strains, and insensitive to stress in either strain. Taken together, these data are in line with behavioural experiments showing ameliorating effects of NK1 and NK2 receptor antagonists against anxiety and depression-like symptoms in rodents, and therefore further implicate the tachykinin systems in the pathophysiology of depression and adult life psychopathology.

Selectively Bred Rodents as Models of Depression and Anxiety

“…A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats (Ryan et al 2009), and unexpectedly maternal separation induced a remodeling of synaptic plasticity only in FSL rats, reducing inhibition of LTP accompanied by marked increase of synaptic NR1 subunit and GluR2/3 subunits of AMPA receptors (Ryan et al 2009). This finding is in line with the demonstration that maternal separation increased the hippocampal cell number, while consistently with this increase, chronic escitalopram treatment reduced the cell number (Petersen et al 2008;Husum et al 2008).…”

Postnatal experiences influence the behavior in adult male and female Fischer and Lewis rats

“…Whereas no difference was found for basal plasma adrenocorticotropin (ACTH) and corticosterone levels, only in MD males an elevated ACTH response to elevated plus‐maze exposure was found indicating that MD effects were more pronounced in males than in females. In the study of Husum et al (2008) the effects of MD on brain peptide levels were explored in Flinders‐Sensitive‐Lines (FSL; a rat genetic model of depression) and Flinders‐Resistant‐Lines (FRL) rats. MD led to long‐term increases in substance P and neurokinin A in the cerebral cortex of adult FSL rats but not in FRL rats.…”

CGRP in a gene–environment interaction model for depression: effects of antidepressant treatment

“…The two supernatants were pooled and freeze-dried and stored at -80°C until radioimmunoassay (RIA). The samples were reconstituted in assay buffer before RIA (26,27,34). , the supernatants were decanted and the pellets were counted in a gamma counter for 3 min.…”

“…The MS procedure has previously been described (12,14,(26)(27)(28). In brief, litters were randomly assigned to either of the two conditions: MS and non-MS.…”