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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Tolerance to low acetylcholinesterase levels: Modification of behavior without acute behavioral change
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Alterations in the hypothalamic-pituitary-adrenal axis in a proposed animal model of depression with genetic muscarinic supersensitivity.
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Selective breeding for increased cholinergic function: Increased serotonergic sensitivity
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Antidepressant effects of rolipram in a genetic animal model of depression: Cholinergic supersensitivity and weight gain
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Enhanced benzodiazepine responsiveness in rats with increased cholinergic function
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Muscarinic binding in suicides
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Diurnal rhythm of core body temperature is phase advanced ina rodent model of depression
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Impaired active avoidance responding in rats selectively bred for increased cholinergic function
Overstreet, D. H., Rezvani, A. H., & Janowsky, D. S. (1990) · Physiology & Behavior · doi:10.1016/0031-9384(90)90097-n · Cited by 33
Dopamine sensitivity in rats selectively bred for increases in cholinergic function
Crocker, A. D., & Overstreet, D. H. (1991) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(91)90596-t · Cited by 32
Dopaminergic and cholinergic influences on motor behavior in chickens.
Sanberg, P. R. (1983) · Journal of comparative psychology · doi:10.1037/0735-7036.97.1.59 · Cited by 27
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Early development of muscarinic supersensitivity in a genetic animal model of depression.
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Neurobiologic effects of bright artificial light
Dilsaver, S. C. (1989) · Brain Research Reviews · doi:10.1016/0165-0173(89)90016-7 · Cited by 24
Enhanced Affective Aggression in Genetically Bred Hypercholinergic Rats
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Effects of Sleep Deprivation on Sleepiness and Increased REM Sleep in Rats Selectively Bred for Cholinergic Hyperactivity
Shiromani, P. J., Velázquez‐Moctezuma, J., Overstreet, D. H., Shalauta, M. D., Lucero, S., & Floyd, C. (1991) · SLEEP · doi:10.1093/sleep/14.2.116 · Cited by 24
Bright artificial light subsensitizes a central muscarinic mechanism
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Mood Disorders: Toward a New Psychobiology
Paykel, E. S. (1985) · American Journal of Psychiatry · doi:10.1176/ajp.142.9.1113 · Cited by 18
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Overstreet, D. H. (1991) · Behavior Genetics · doi:10.1007/bf01067667 · Cited by 17
Absence of Anticholinergic Activity of Rolipram, an Antidepressant with a Novel Mechanism of Action, in three Different Animal Models in Vivo
Wachtel, H., Löschmann, P.-A., & Pietzuch, P. (1988) · Pharmacopsychiatry · doi:10.1055/s-2007-1014679 · Cited by 16
Effects of bright light on responsiveness to a muscarinic agonist in rats selectively bred for endogenously increased cholinergic function
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The Flinders Sensitive Line exhibits enhanced thermic responsiveness to nicotine relative to the Sprague-Dawley rat.
Dilsaver, S., Peck, J., & Overstreet, D. (1992) · Pharmacology, Biochemistry and Behavior · doi:10.1016/0091-3057(92)90053-i · Cited by 14
A Study to Assess The Anticholinergic Activity of Rolipram in Healthy Elderly Volunteers
Ross, C. J., Toon, S., Rowland, M., Murray, G. R., & Meya, U. (1988) · Pharmacopsychiatry · doi:10.1055/s-2007-1021946 · Cited by 14
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A Cholinergic Supersensitivity Model of Depression
Overstreet, D. H., & Janowsky, D. S. (2003) · Humana Press eBooks · doi:10.1385/0-89603-177-2:81 · Cited by 14
Studies of a possible relationship of brain proteins to changes in behavioral sensitivity to DFP
Sihotang, K., & Overstreet, D. H. (1983) · Life Sciences · doi:10.1016/0024-3205(83)90088-7 · Cited by 13
Preclinical and clinical studies with corticotropin-releasing factor: implications for affective disorders.
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Bright light blocks amitriptyline-induced cholinoceptor supersensitivity
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EFFECTS OF ACUTE AND CHRONIC STRESSORS ON SACCHARIN PREFERENCE IN HYPERCHOLINERGIC RATS
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Relation between the thermoregulatory effects of intracerebroventricularly injected dopamine and 5-hydroxytryptamine in the rabbit
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Genetic Animal Models of Endogenous Depression
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Amitriptyline-induced supersensitivity of a central muscarinic mechanism: Lithium blocks Amitriptyline- induced supersensitivity
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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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