Cited by 370Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionStress Responses and Cortisol

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The flinders sensitive line rats: A genetic animal model of depression

Overstreet, David H.·1993·Neuroscience & Biobehavioral Reviews

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Abstract

The Flinders Sensitive Line (FSL) rat, selectively bred for increased responses to the anticholinesterase DFP, was originally proposed as an animal model of depression because, like depressed humans, it is supersensitive to the behavioral and hormonal effects of cholinergic (muscarinic) agonists. The present review critically examines earlier and recent data collected on FSL rats to assess whether the model has good face, construct and/or predictive validity. With respect to face validity, FSL rats resemble depressed humans, at least superficially, in that they demonstrate: (a) reduced locomotor activity, (b) reduced body weight, (c) increased REM sleep, and (d) cognitive (learning) difficulties. So far, studies designed to assess the presence of anhedonia, a cardinal symptom of melancholic depression, have been inconclusive, but there are trends for the FSL rats to be more anhedonic than their control counterparts, the Flinders Resistant Line (FRL) rats, when exposed to chronic mild stress. Thus, FSL rats fulfill the criterion of face validity. Because FSL rats also are more sensitive to cholinergic agonists and have phase advanced circadian rhythms, they meet the criteria for the cholinergic and circadian rhythm models of depression and, therefore, have good construct validity. A key behavioral symptom exhibited by the FSL rat is demonstration of an exaggerated immobility when exposed to stressors such as foot shock and forced swimming. This behavioral abnormality has been normalized by a number of well-recognized antidepressant drugs such as imipramine and desipramine, as well as newer generation antidepressants with promising clinical effects such as sertraline and rolipram. However, several treatments that have not been routinely used to treat depression (lithium, exposure to bright light, the anticholinesterase DFP) have been ineffective in reversing the exaggerated immobility. Thus, the evidence in the present review indicates that the FSL rat model of depression fulfills the criteria of face, construct, and predictive validities.

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Background
Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression
Overstreet, D. H., Keeney, A. J., & Hogg, S. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.04.010 · Cited by 104
Links Between Depression and Substance Abuse in Adolescents
Rao, U. (2006) · American Journal of Preventive Medicine · doi:10.1016/j.amepre.2006.07.002 · Cited by 106
Imipramine treatment increases the number of hippocampal synapses and neurons in a genetic animal model of depression
Chen, F., Madsen, T. M., Wegener, G., & Nyengaard, J. R. (2009) · Hippocampus · doi:10.1002/hipo.20718 · Cited by 105
Alterations in neuropeptide Y levels and Y1 binding sites in the Flinders Sensitive Line rats, a genetic animal model of depression
Caberlotto, L., Jimenez, P., Overstreet, D. H., Hurd, Y. L., Mathé, A. A., & Fuxé, K. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00234-7 · Cited by 100
Aggressive behavior and HPA axis hormones after social isolation in adult rats of two different genetic animal models for depression
Malkesman, O., Maayan, R., Weizman, A., & Weller, A. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.09.017 · Cited by 98
Mapping the differences in the brain concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression
Angelucci, F., Aloe, L., Jiménez-Vasquez, P. A., & Mathé, A. A. (2000) · Neuroreport · doi:10.1097/00001756-200004270-00044 · Cited by 97
A Review of Biomarkers in Mood and Psychotic Disorders: A Dissection of Clinical vs. Preclinical Correlates
Brand, S., Moller, M., & Harvey, B. (2015) · Current Neuropharmacology · doi:10.2174/1570159x13666150307004545 · Cited by 95
“the FSL rat [79], Wistar Kyoto rat [80] and mice bred for spontaneous helplessness [81].”
Background
Topiramate Normalizes Hippocampal NPY-LI in Flinders Sensitive Line ‘Depressed’ Rats and Upregulates NPY, Galanin, and CRH-LI in the Hypothalamus: Implications for Mood-Stabilizing and Weight Loss-Inducing Effects
Husum, H., van Kammen, D., Termeer, E. H., Bolwig, T. G., & Mathé, A. A. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300178 · Cited by 96
“The observed decrease of CRH-LI in the hippocampus may possibly reflect aspects of the impaired learning performance and cognitive deficits, which are previously described features of the FSL rat (Yadid et al, 2000; Overstreet, 1993).”
BackgroundInfluential
Faecal microbiota transplantation from patients with depression or healthy individuals into rats modulates mood-related behaviour
Knudsen, J. K., Michaelsen, T. Y., Bundgaard‐Nielsen, C., Nielsen, R. E., Hjerrild, S., Leutscher, P. D. C., Wegener, G., & Sørensen, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-01248-9 · Cited by 99
Stress-Related Alterations of Visceral Sensation: Animal Models for Irritable Bowel Syndrome Study
Larauche, M. H., Mulak, A., & Taché, Y. (2011) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm.2011.17.3.213 · Cited by 92
“The influence of cognitive aspects as well as motivational and emotional components on the processing of sensory information is mediated by extensive neuro-anatomical network with a pivotal role of the insular and anterior cingulate cortices.9,187,188 Autonomic dysfunction, in particular decreased parasympathetic acti…”
Method
Neuropeptide expression in rats exposed to chronic mild stresses
Sergeyev, V., Fetissov, S. O., Mathé, A. A., Jimenez, P. A., Bartfai, T., Mortas, P., Gaudet, L., Moreau, J., & H�kfelt, T. (2004) · Psychopharmacology · doi:10.1007/s00213-004-2015-3 · Cited by 95
“The FSL model is well established and expresses alterations in neurotransmitter functions that have been implicated in depressive disorders (Overstreet 1993; Janowsky et al. 1994).”
BackgroundMethodInfluential
Neuropeptide Y in male and female brains of flinders sensitive line, a rat model of depression. Effects of electroconvulsive stimuli
Jiménez-Vasquez, P. A., Overstreet, D. H., & Mathé, A. A. (2000) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(00)00036-4 · Cited by 91
“Neuropeptide Y (NPY), is a 36 amino acid neuropeptide discovered by Tatemoto and Mutt (1980), and together with its receptors (Y1±Y5) is widely but selectively distributed in the central nervous system (CNS).”
Background
MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation
Mouri, A., Sasaki, A., Watanabe, K., Sogawa, C. A., Kitayama, S., Mamiya, T., Miyamoto, Y., Yamada, K., Noda, Y., & Nabeshima, T. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6458-11.2012 · Cited by 89
“Decreased locomotor activity is observed in some animal models of depression as a symptom of psychomotor retardation related to diminished interest (Willner, 1991; Overstreet, 1993).”
Background
The Flinders Sensitive Line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17β-estradiol
Österlund, M. K., Overstreet, D. H., & Hurd, Y. L. (1999) · Molecular Brain Research · doi:10.1016/s0169-328x(99)00274-0 · Cited by 87
The Fawn-Hooded (FH/Wjd) rat: a genetic animal model of comorbid depression and alcoholism
Rezvani, A. H., Parsian, A., & Overstreet, D. H. (2002) · Psychiatric Genetics · doi:10.1097/00041444-200203000-00001 · Cited by 86
“In general, animal models can be judged on the basis of how well they satisfy three major criteria (Overstreet, 1993; Willner, 1997).”
Background
White Paper: Neuropsychiatric Aspects of Sensitivity to Low-Level Chemicals: A Neural Sensitization Model
Bell, I. R. (1994) · Toxicology and Industrial Health · doi:10.1177/074823379401000502 · Cited by 84
Blunted accumbal dopamine response to cocaine following chronic social stress in female rats: exploring a link between depression and drug abuse
Shimamoto, A., DeBold, J. F., Holly, E. N., & Miczek, K. A. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2364-7 · Cited by 81
“In fact, the Flinders sensitive line of rats, a genetic model of depression (Overstreet 1993), had higher amount of 5-HT in the NAc compared to controls (Zangen et al.”
Two Different Putative Genetic Animal Models of Childhood Depression
Malkesman, O., Braw, Y., Maayan, R., Weizman, A., Overstreet, D. H., Shabat-Simon, M., Kesner, Y., Touati-Werner, D., Yadid, G., & Weller, A. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.05.039 · Cited by 81
Traumatic Brain Injury – Modeling Neuropsychiatric Symptoms in Rodents
Malkesman, O., Tucker, L. B., Ozl, J., & McCabe, J. T. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00157 · Cited by 85
Effects of Seasonal Allergic Rhinitis on Fatigue Levels and Mood
Marshall, P. S., O’Hara, C., & Steinberg, P. (2002) · Psychosomatic Medicine · doi:10.1097/01.psy.0000021944.35402.44 · Cited by 80
“These rats are selectively bred for CNS cholinergic hypersensitivity and represent a major genetic model of depression (31).”
Background
Neuropeptide Y, neurokinin A and neurotensin in brain regions of Fawn Hooded “depressed”, wistar, and Sprague dawley rats. Effects of electroconvulsive stimuli
Mathé, A. A., Jimenez, P. A., Theodorsson, E., & Stenfors, C. (1998) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(98)00023-2 · Cited by 81
The Forced Swim Test for Depression-Like Behavior in Rodents
Kraeuter, A.-K., Guest, P. C., & Sarnyai, Z. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8994-2_5 · Cited by 85
Two different putative genetic animal models of childhood depression—A review
Malkesman, O., & Weller, A. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.03.003 · Cited by 81
“Overstreet (1993) and Yadid et al. (2000) reported longer immobility durations in adult FSL male rats compared to controls, using the modified, one session procedure.”
Influential
Possible confounding influence of strain, age and gender on cognitive performance in rats.
Andrews, J. (1996) · Brain research. Cognitive brain research · doi:10.1016/0926-6410(96)00011-0 · Cited by 96
Behavioral Similarities and Differences among Alcohol‐Preferring and ‐Nonpreferring Rats: Confirmation by Factor Analysis and Extension to Additional Groups
Overstreet, D. H., Halikas, J. A., Середенин, С. Б., Kampov‐Polevoy, A. B., Viglinskaya, K. V., Kashevskaya, O. P., Badishtov, B. A., Knapp, D. J., Mormède, P., Kiianmaa, K., et al. (1997) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1997.tb03847.x · Cited by 79
Performance of four different rat strains in the autoshaping, two-object discrimination, and swim maze tests of learning and memory
Andrews, J. S., Jansen, J. H. M., Linders, S., Princen, A., & Broekkamp, C. L. E. (1995) · Physiology & Behavior · doi:10.1016/0031-9384(94)00336-x · Cited by 90
Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress
Murphy‐Royal, C., Gordon, G. R., & Bains, J. S. (2019) · Glia · doi:10.1002/glia.23610 · Cited by 80
“The Flinders sensitive line of rats was developed specifically for its hypersensitivity to cholinergic agonists, similar to human depressive patients, and depressive-like phenotypes (Overstreet, 1993).”
Background
Programmed Acute Electrical Stimulation of Ventral Tegmental Area Alleviates Depressive-Like Behavior
Friedman, A., Frankel, M., Flaumenhaft, Y., Merenlender, A., Pinhasov, A., Feder, Y., Taler, M., Gil‐Ad, I., Abeles, M., & Yadid, G. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.177 · Cited by 78
“Depressive-like behavior (despair) was measured by calculation of immobility time using a modified version of the Porsolt forced swim test (Dremencov et al, 2006; Overstreet, 1993; Overstreet et al, 2005).”
Method
What do we know about sex differences in depression: A review of animal models and potential mechanisms
Ma, L., Xu, Y., Wang, G., & Li, R. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.08.026 · Cited by 83
“The rats were found to have poorer adaptive capacity to mild stressors than regular rats and several antidepressants such as TCAs and SSRIs were found to promote the depressive-like symptoms (Overstreet, 1993).”
Reward and anxiety in genetic animal models of childhood depression
Malkesman, O., Braw, Y., Zagoory‐Sharon, O., Golan, O., Lavi‐Avnon, Y., Schroeder, M., Overstreet, D. H., Yadid, G., & Weller, A. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2005.04.023 · Cited by 77
Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenic seizures
Sarkisova, K. Y., & Куликов, М. А. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2005.07.024 · Cited by 74
Animal Models of Depressive Illness: The Importance of Chronic Drug Treatment
Mitchell, P. B., & Redfern, P. H. (2005) · Current Pharmaceutical Design · doi:10.2174/1381612053382250 · Cited by 77
“Relative to the control Flinders Resistant Line, FSL animals have a number of characteristics reminiscent of depression, including cholinergic supersensitivity, increased REM sleep, and reduced locomotor activity, which is further pronounced following electric footshock [76].”
Background
Neuropeptide Y in brains of the Flinders Sensitive Line rat, a model of depression. Effects of electroconvulsive stimuli and d-amphetamine on peptide concentrations and locomotion
Jiménez-Vasquez, P. A., Salmi, P., Ahlénius, S., & Mathé, A. A. (2000) · Behavioural Brain Research · doi:10.1016/s0166-4328(00)00142-x · Cited by 73

Authors: Overstreet, D. H.
Affiliations: University of North Carolina at Chapel Hill (US)
Corresponding author: Overstreet, David H.
Venue: Neuroscience & Biobehavioral Reviews
Publisher: Elsevier BV
Published: 1993-03
Volume: 17
Issue: 1
Pages: 51-68
ISSN: 0149-7634 (ISSN-L)
DOI: 10.1016/s0149-7634(05)80230-1
OpenAlex: W1991527095
Cited by: 369
References: 170
Citations by year: 2026: 3 · 2025: 3 · 2024: 7 · 2023: 2 · 2022: 6 · 2021: 10 · 2020: 11 · 2019: 5 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 13 · 2014: 8 · 2013: 18 · 2012: 9
FWCI: 2.77
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuroscience & Biobehavioral Reviews (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: Flinders Sensitive Line rats, animal models of depression, anhedonia, chronic mild stress, immobility, antidepressant efficacy, circadian rhythm, locomotor activity, REM sleep, face validity, construct validity, predictive validity
MeSH terms: Animals, Depression, Disease Models, Animal, Rats, Inbred Strains, Rats

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The flinders sensitive line rats: A genetic animal model of depression

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