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
Acute stress differentially affects corticotropin-releasing hormone mRNA expression in the central amygdala of the “depressed” flinders sensitive line and the control flinders resistant line rats
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Background
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“J Pharmacol Exp Ther 315:1163 1171, Epub 2005 Aug 25 Overstreet DH, Rezvani AH, Janowsky DS (1992) Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism.”
Background
Post-weaning Social Isolated Flinders Sensitive Line Rats Display Bio-Behavioural Manifestations Resistant to Fluoxetine: A Model of Treatment-Resistant Depression
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Background
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“…et al., 1991), cognitive deficits and learning disturbances (Overstreet, 1993), and increased immobility in the Porsolt swim test which is reversible by chronic but not acute treatment with antidepressant drugs (for reviews see Overstreet, 1986, 1993 ; Overstreet et al., 2005 ; Yadid et al., 2000).”
BackgroundInfluential
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Method
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“They were more immobile in the forced swim test (Overstreet, 1993, 2002) but not in the elevated plusmaze (Schiller et al., 1991) or prepulse inhibition of startle (Markou et al., 1994).”
BackgroundMethod
Reduced Primary Antibody Responses in a Genetic Animal Model of Depression
Friedman, E. M., Becker, K. A., Overstreet, D. H., & Lawrence, D. A. (2002) · Psychosomatic Medicine · doi:10.1097/00006842-200203000-00009 · Cited by 19
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BackgroundResult
Dehydroepiandrosterone in the nucleus accumbens is associated with early onset of depressive-behavior: A study in an animal model of childhood depression
Malkesman, O., Shayit, M., Genud, R., Zangen, A., Kinor, N., Maayan, R., Weizman, A., Weller, A., & Yadid, G. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.06.031 · Cited by 18
Natural and Cellular Immune Responses in Flinders Sensitive and Resistant Line Rats
Friedman, E. M. (1996) · Neuropsychopharmacology · doi:10.1016/0893-133x(95)00235-6 · Cited by 18
Altered neuroendocrine response and gastric dysmotility in the Flinders Sensitive Line rat
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Monoamines, BDNF, Dehydroepiandrosterone, DHEA-Sulfate, and Childhood Depression—An Animal Model Study
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“Overstreet [43] and Yadid [44] have shown longer immobility durations in adult Flinders Sensitive Line (FSL) male rats compared to controls, using the modified “Porsolt” paradigm—a one-session procedure.”
Method
Sex-dependent behavior, neuropeptide profile and antidepressant response in rat model of depression
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“FSL rats weigh less [12,13], are less active in an open field (OF) [12,14], are less anxious [15], show a decreased sensitivity to rewards under stress [16], and show increased immobility in the forced swim test (FST) [17,18], a classical model of depressive-like behavior.”
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Expression and function of striatal nAChRs differ in the Flinders sensitive (FSL) and resistant (FRL) rat lines
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A Maternal High-Fat Diet Causes Anxiety-Related Behaviors by Altering Neuropeptide Y1 Receptor and Hippocampal Volumes in Rat Offspring: the Potential Effect of N-Acetylcysteine
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Acute citalopram has different effects on regional 5-HT synthesis in FSL, FRL, and SDP rats: An autoradiographic evaluation
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Evaluation of the relationship between hyperinsulinaemia and myocardial ischaemia/reperfusion injury in a rat model of depression
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Peptidyl epoxides as selective protease inactivators
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“…such as Flinders Sensitive Line of genetically sensitized rats to diisopropyl fluorophosphate (DFP, which inhibit organophosphorus cholinesterase (Overstreet 1993)), or lipopolysaccharidetreated rats, treatment with ICV anti-ouabain antibodies also improves depressive symptoms (Goldstein et al.”
Background
Gene-environment interactions in a rat model of depression. Maternal separation affects neurotensin in selected brain regions
Ellenbroek, B. A., Angelucci, F., Husum, H., & Mathé, A. A. (2016) · Neuropeptides · doi:10.1016/j.npep.2016.05.001 · Cited by 15
Behavioral and metabolic effects of S-adenosylmethionine and imipramine in the Flinders Sensitive Line rat model of depression
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“001), which is characteristic for their depressive-like phenotype [20].”
Behavioral effects of the CRF1 receptor antagonist R121919 in rats selectively bred for high and low activity in the swim test
Gutman, D. A., Coyer, M. J., Boss-Williams, K. A., Owens, M. J., Nemeroff, C. B., & Weiss, J. M. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.05.003 · Cited by 14
“Similar to our SwLo animals, the Flinders Sensitive Line rat shows more immobility on the forced swim test relative to its control counterpart, the Flinders Resistant Line (Overstreet, 1993, 2002).”
Modelling occupational stress and health: the impact of the demand–control model on academic research and on workplace practice
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Prediction of Individual Vulnerability to Stress-induced Gastric Ulcerations in Rats: A Factor Analysis of Selected Behavioral and Biological Indices
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MicroRNAs as potential diagnostic biomarkers for bipolar disorder
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“…al. (2017) had included miRNA expression in EVs extracted from the brains of Flinders Sensitive Line rats, as a genetic animal model of depression (Overstreet, 1993), and the altered expression of miR-149 and miR-29c supported the findings in EVs from anterior cingulate cortex of patients with BD…”
Behavioural Consequences of P‐Glycoprotein Deficiency in Mice, with Special Focus on Stress‐Related Mechanisms
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Antagonism of anticholinesterase (DFP) toxicity by donepezil plus scopolamine: a preliminary study
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“Flinders rats are a genetic model of depression, derived by selective breeding of Sprague-Dawley (SD) rats for their hypersensitivity or resistance to treatment with the anticholinesterase diisopropylfluorophosphate (DFP) [9,10] to derive Flinders Sensitive (FSL) and Flinders Resistant (FRL) lines [11].”
Enhanced expression of the neuronal K+/Cl− cotransporter, KCC2, in spontaneously depressed Flinders Sensitive Line rats
Matrisciano, F., Nasca, C., Molinaro, G., Riozzi, B., Scaccianoce, S., Raggi, M. A., Mercolini, L., Biagioni, F., Mathé, A. A., Sanna, E., et al. (2010) · Brain Research · doi:10.1016/j.brainres.2010.02.017 · Cited by 13
“…at the forced swim test and other “depressive features” such as psychomotor retardation, reduced appetite, increased REM sleep, and abnormalities in dopaminergic and noradrenergic neurotransmission (Overstreet and Russell 1982; Overstreet, 1993; Zangen et al., 1999, 2002; Matrisciano et al., 2008).”
Long-term lithium administration abolishes the resistance to stress in rats sensitized to morphine
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Links between multiple chemical sensitivity and asthma in a rat model of cholinergic hypersensitivity: a brief review
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Depression
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“*p 0.05 compared to those of control animals 1 3 Flinders sensitive rat line, which is a genetic model of depression (Overstreet 1993), produced lower “burst” firing in their VTA DA neurons (Friedman et al.”
Influential
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Neurobiology of Affective Disorders
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Repeated cannabidiol treatment affects neuroplasticity and endocannabinoid signaling in the prefrontal cortex of the Flinders Sensitive Line (FSL) rat model of depression.
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“2007) to depression (Overstreet 1993), and more recently the potential of cell therapy to restore function to the body following spinal cord damage (Rasiman and Li 2007; Chen et al.”
Background
New Horizons for Phenotyping Behavior in Rodents: The Example of Depressive-Like Behavior
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“…recapitulate (either in isolation or in a combined mode) such processes through selective breeding (e.g., the Flinder’s sensitive line of rats; Overstreet, 1993) or genetic engineering (see for review Cryan and Mombereau, 2004; Lucki, 2011; Planchez et al., 2019; Scherma et al., 2019), as…”
Background
Dehydroepiandrosterone and monoamines in the limbic system of a genetic animal model of childhood depression
Malkesman, O., Braw, Y., Ram, E., Maayan, R., Weizman, A., Kinor, N., Yadid, G., & Weller, A. (2007) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2007.06.007 · Cited by 10
“The increased immobility was prevented by chronic (but not acute) antidepressant treatment (Overstreet, 1993).”
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“Moreover, FSL rats show decreased appetite and weigh less compared to controls (Overstreet, 1993, 2002).”
Background
A novel butyrylcholinesterase inhibitor induces antidepressant, pro-cognitive, and anti-anhedonic effects in Flinders Sensitive Line rats: The role of the ghrelin-dopamine cascade
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What have we learned about sleep from selective breeding strategies?
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Altered physiology of acid secretion in depression‐prone Flinders rats results in exacerbated NSAID and stress‐induced gastric damage
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Autonomic and behavioral responses of selectively bred hypercholinergic rats to oxotremorine and diisopropyl fluorophosphate
Rezvani, A. H., Overstreet, D. H., Ejantkar, A., & Gordon, C. J. (1994) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(94)90336-0 · Cited by 7

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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