title: 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.
authors.affiliation: Lundbeck, Disease Pharmacology, Psychopharmacology, Valby, Denmark.
authors.forename: Henriette
authors.initials: H
authors.lastname: Husum
authors.forename: Gitta
authors.initials: G
authors.lastname: Wörtwein
authors.forename: Weronika
authors.initials: W
authors.lastname: Andersson
authors.forename: Tom G
authors.initials: TG
authors.lastname: Bolwig
authors.forename: Aleksander A
authors.initials: AA
authors.lastname: Mathé
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D001010:Anxiety, Separation / Q000378:metabolism / Q000523:psychology; D001835:Body Weight / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism*; D003863:Depression / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D018728:Entorhinal Cortex / Q000378:metabolism*; D007120:Immunochemistry; D008297:Male; D015288:Neurokinin A / Q000235:genetics* / Q000378:metabolism*; D009778:Occipital Lobe / Q000378:metabolism; D009929:Organ Size / Q000502:physiology; D010487:Periaqueductal Gray / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012934:Social Isolation; D013373:Substance P / Q000235:genetics* / Q000378:metabolism*
chemical_list: D013373:Substance P; D015288:Neurokinin A; D003346:Corticotropin-Releasing Hormone