title: Female Flinders Sensitive Line rats show estrous cycle-independent depression-like behavior and altered tryptophan metabolism.
abstract: Clinical studies suggest a link between depression and dysfunctional tryptophan (TRP) metabolism. Even though depression is twice as prevalent in women as men, the impact of the estrous cycle on TRP metabolism is not well-understood. Here we investigated 13 kynurenine and serotonin metabolites in female Flinders Sensitive Line (FSL) rats, a genetic rat model of depression. FSL rats and controls (Flinders Resistant Line rats), 12-20weeks old, were subject to the forced swim test (FST), a commonly used measure of depression-like behavior. Open field was used to evaluate locomotor ability and agoraphobia. Subsequently, plasma and hemispheres were collected and analyzed for their content of TRP metabolites using liquid chromatography-tandem mass spectrometry. Vaginal saline lavages were obtained daily for ⩾2 cycles. To estimate the effects of sex and FST we included plasma from unhandled, naïve male FSL and FRL rats. Female FSL rats showed a depression-like phenotype with increased immobility in the FST, not confounded by anxiety. In the brain, 3-hydroxykynurenine was increased whereas anthranilate and 5-hydroxytryptophan were decreased. In plasma, anthranilate and quinolinate levels were lower in FSL rats compared to the control line, independent of sex and FST. The estrous cycle neither impacted behavior nor TRP metabolite levels in the FSL rat. In conclusion, the female FSL rat is an interesting preclinical model of depression with altered TRP metabolism, independent of the estrous cycle. The status of the pathway in brain was not reflected in the plasma, which may indicate that an inherent local, cerebral regulation of TRP metabolism occurs.
authors.affiliation: Translational Neuropsychiatry Unit, Institute for Clinical Medicine, Aarhus University, Skovagervej 2, 8240 Risskov, Denmark; Lundbeck Research USA, 215 College Road, Paramus NJ 07652, USA. Electronic address: ares@clin.au.dk.
authors.forename: Amanda
authors.initials: A
authors.lastname: Eskelund
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus NJ 07652, USA. Electronic address: dpbu.lundbeck@gmail.com.
authors.forename: David P
authors.initials: DP
authors.lastname: Budac
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus NJ 07652, USA. Electronic address: connie_sanchez@clin.au.dk.
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Translational Neuropsychiatry Unit, Institute for Clinical Medicine, Aarhus University, Skovagervej 2, 8240 Risskov, Denmark. Electronic address: betina.elfving@clin.au.dk.
authors.forename: Betina
authors.initials: B
authors.lastname: Elfving
authors.affiliation: Translational Neuropsychiatry Unit, Institute for Clinical Medicine, Aarhus University, Skovagervej 2, 8240 Risskov, Denmark. Electronic address: Wegener@clin.au.dk.
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003866:Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D030762:Estrous Cycle / Q000378:metabolism*; D005260:Female; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000502:physiology; D017378:Quinolinic Acid / Q000097:blood; D051381:Rats; D055500:Resilience, Psychological; D012727:Sex Characteristics; D014364:Tryptophan / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000378:metabolism
chemical_list: D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D006916:5-Hydroxytryptophan; D017378:Quinolinic Acid
keywords: 3-hydroxykynurenine; Flinders Sensitive Line rat; depression; estrous cycle; serotonin pathway; tryptophan–kynurenine pathway