The Flinders sensitive line rats: a genetic animal model of depression

Overstreet, David H.

doi:10.1016/s0149-7634(05)80230-1

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

The Flinders sensitive line rats: a genetic animal model of depression

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

DOI 10.1016/s0149-7634(05)80230-1

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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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In rodent studies, the Flinders rat model was selected for its sensitivity to challenge with an AChE inhibitor, and sensitive rats also display a constellation of depression-like endophenotypes.
“In rodent studies, the Flinders rat model was selected for its sensitivity to challenge with an AChE inhibitor, and sensitive rats also display a constellation of depression-like endophenotypes, supporting the idea that increasing ACh levels increases symptoms of depression (Overstreet, 1993).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Overstreet, 1993

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Casebolt, T. L., & Jope, R. S. (1989) · Biological Psychiatry · doi:10.1016/0006-3223(89)90180-7 · Cited by 73 · see citing works
Selective breeding for sensitivity to DFP: Generalization of effects beyond criterion variables
Russell, R. W., Overstreet, D. H., Messenger, M., & Helps, S. C. (1982) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(82)90466-x · Cited by 72 · see citing works
Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains
Puciłowski, O., & Overstreet, D. H. (1993) · Brain Research Bulletin · doi:10.1016/0361-9230(93)90293-k · Cited by 72 · see citing works
Immobility-reducing effects of antidepressants in a genetic animal model of depression
Schiller, G. D., Puciłowski, O., Wienicke, C., & Overstreet, D. H. (1992) · Brain Research Bulletin · doi:10.1016/0361-9230(92)90267-2 · Cited by 70 · see citing works
Evidence for a cholinergic role in haloperidol-induced catalepsy
Klemm, W. R. (1985) · Psychopharmacology · doi:10.1007/bf00428402 · Cited by 70 · see citing works
Depression, suicide, and aggression in alcoholics and their relationship to plasma amino acids
Branchey, L., Branchey, M. H., Shaw, S., & Lieber, C. S. (1984) · Psychiatry Research · doi:10.1016/0165-1781(84)90027-1 · Cited by 68 · see citing works
Mood Disorders: Toward a New Psychobiology
Whybrow, P. C., Akiskal, H. S., & McKinney, W. T. (1984) · Cited by 67 · see citing works
3-Methoxy-4-hydroxyphenylglycol in depression
Shaw, D. M., O'Keeffe, R., Macsweeney, D. A., Brooksbank, B. W. L., Noguera, R., & Coppen, A. J. (1973) · Psychological Medicine · doi:10.1017/s003329170004962x · Cited by 67 · see citing works
A dopamine‐5‐hydroxytryptamine link in the hypothalamic pathways which mediate heat loss in the rat.
Cox, B., Kerwin, R. W., Lee, T. F., & PYCOCK, C. (1980) · The Journal of Physiology · doi:10.1113/jphysiol.1980.sp013266 · Cited by 64 · see citing works
Rolipram versus lmipramine in Inpatients with Major, ???Minor??? or Atypical Depressive Disorder: A Double-Blind Double-Dummy Study Aimed at Testing a Novel Therapeutic Approach
Bertolino, A., Crippa, D., Dio, S. D., Fichte, K., Musmeci, G., PORRO, V., Rapisarda, V., Sastre-y-Hernández, M., & Schratzer, M. (1988) · International Clinical Psychopharmacology · doi:10.1097/00004850-198807000-00006 · Cited by 64 · see citing works
Tolerance to low acetylcholinesterase levels: Modification of behavior without acute behavioral change
Chippendale, T. J., Zawolkow, G. A., Russell, R. W., & Overstreet, D. H. (1972) · Psychopharmacology · doi:10.1007/bf00422099 · Cited by 62 · see citing works
CHOLINERGIC INHIBITION OF SELF-STIMULATION BEHAVIOR
Domino, E. F., & OLDS, M. E. (1968) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)28118-6 · Cited by 61 · see citing works
Dysbalance of neuronal second messenger function in the aetiology of affective disorders: A pathophysiological concept hypothesising defects beyond first messenger receptors
Wachtel, H. (1989) · Journal of Neural Transmission · doi:10.1007/bf01250641 · Cited by 55 · see citing works
The association of supersensitive cholinergic rem-induction and affective illness within pedigrees
Sitaram, N., Dubé, S., Keshavan, M. S., Davies, A., & Reynal, P. (1987) · Journal of Psychiatric Research · doi:10.1016/0022-3956(87)90097-5 · Cited by 54 · see citing works
Possible receptor effects of chronic lithium administration
Bunney, W. E. (1983) · Neuropharmacology · doi:10.1016/0028-3908(83)90185-5 · Cited by 50 · see citing works
Mitogen-stimulated lymphocyte proliferation and pituitary hormones in major depression
Darko, D. F., Gillin, J. C., Risch, S. C., Bulloch, K., Golshan, S., Tasevska, Z., & Hamburger, R. N. (1989) · Biological Psychiatry · doi:10.1016/0006-3223(89)90018-8 · Cited by 49 · see citing works
Benzodiazepine receptors in the central nervous system.
Skolnick, P., & Paul, S. (1982) · International review of neurobiology · doi:10.1016/s0074-7742(08)60623-6 · Cited by 49 · see citing works
Effects of cholinergic agonists and antagonists on self-stimulation behavior in the rat.
Newman, L. M. (1972) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0032830 · Cited by 48 · see citing works
How generalizable are the results of clinical trials?
Nr, S. (1980) · PubMed · Cited by 48 · see citing works
Changes of acetylcholinesterase activity in three major brain areas and related changes in behaviour following acute treatment with diisopropyl fluorophosphate
Kozar, M. D., Overstreet, D. H., Chippendale, T. C., & Russel, R. W. (1976) · Neuropharmacology · doi:10.1016/0028-3908(76)90131-3 · Cited by 47 · see citing works
Alterations in the hypothalamic-pituitary-adrenal axis in a proposed animal model of depression with genetic muscarinic supersensitivity.
Owens, M. J., Overstreet, D. H., Knight, D. L., Rezvani, A. H., Ritchie, J., Bissette, G., Janowsky, D. S., & Nemeroff, C. B. (1991) · PubMed · Cited by 46 · see citing works
Selective breeding for increased cholinergic function: Increased serotonergic sensitivity
Wallis, E., Overstreet, D. H., & Crocker, A. D. (1988) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(88)90356-5 · Cited by 46 · see citing works
Cholinergic-dopaminergic interactions in experimental catalepsy
Klemm, W. R. (1983) · Psychopharmacology · doi:10.1007/bf00439268 · Cited by 43 · see citing works
Antidepressant effects of rolipram in a genetic animal model of depression: Cholinergic supersensitivity and weight gain
Overstreet, D. H., Double, K. L., & Schiller, G. D. (1989) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(89)90260-8 · Cited by 42 · see citing works
Measuring cholinergic sensitivity: I. Arecoline effects in bipolar patients
Nürnberger, J. I., Berrettini, W. H., Mendelson, W. B., Sack, D. A., & Gershon, E. S. (1989) · Biological Psychiatry · doi:10.1016/0006-3223(89)90221-7 · Cited by 41 · see citing works
Brain serotonergic neurons: Their role in a form of dominance-subordination behavior in rats
Kostowski, W., Plewako, M., & Bidziński, A. (1984) · Physiology & Behavior · doi:10.1016/0031-9384(84)90155-0 · Cited by 41 · see citing works
Lack of anxiety in an animal model of depression with cholinergic supersensitivity
Schiller, G. D., Daws, L. C., Overstreet, D. H., & Orbach, J. (1991) · Brain Research Bulletin · doi:10.1016/0361-9230(91)90019-g · Cited by 40 · see citing works
Enhanced elevation of corticosterone following arecoline administration to rats selectively bred for increased cholinergic function
Overstreet, D. H., Booth, R. A., Dana, R. C., Risch, S. C., & Janowsky, D. S. (1986) · Psychopharmacology · doi:10.1007/bf00310528 · Cited by 40 · see citing works
GABA, depression and the mechanism of action of antidepressant drugs: a neuroendocrine approach
Monteleone, P., Maj, M., Iovino, M., & Steardo, L. (1990) · Journal of Affective Disorders · doi:10.1016/0165-0327(90)90043-8 · Cited by 40 · see citing works
New perspectives on the molecular pharmacology of affective disorders
Sulser, F. (1989) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/bf00449803 · Cited by 39 · see citing works
The serotonin/norepinephrine-link in brain. II. Role of serotonin in the regulation of beta adrenoceptors in the low agonist affinity conformation.
Gillespie, D. D., Manier, D. H., Sanders‐Bush, E., & Sulser, F. (1988) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)24229-x · Cited by 38 · see citing works
GABA and affective disorders.
Kg, L., Pl, M., & Bartholini, G. (1987) · PubMed · Cited by 38 · see citing works
Rat strain differences in response to dark pulse triggering of paradoxical sleep
Benca, R. M., Bergmann, B. M., Leung, C. G., Nummy, D., & Rechtschaffen, A. (1991) · Physiology & Behavior · doi:10.1016/0031-9384(91)90235-g · Cited by 35 · see citing works
Enhanced benzodiazepine responsiveness in rats with increased cholinergic function
Pepe, S., Overstreet, D. H., & Crocker, A. D. (1988) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(88)90304-8 · Cited by 35 · see citing works
Muscarinic binding in suicides
Kaufmann, C. A., Gillin, J. C., Hill, B., O'Laughlin, T., Phillips, I., Kleinman, J. E., & Wyatt, R. J. (1984) · Psychiatry Research · doi:10.1016/0165-1781(84)90137-9 · Cited by 34 · see citing works
The effect of antidepressant drugs on dominance behavior in rats competing for food.
Malatyńska, E., & Kostowski, W. (1985) · PubMed · Cited by 34 · see citing works
Selective breeding for increased cholinergic function: biometrical genetic analysis of muscarinic responses.
Overstreet, D. H., Russell, R. W., Hay, D. A., & Crocker, A. D. (1992) · PubMed · Cited by 33 · see citing works
Diurnal rhythm of core body temperature is phase advanced ina rodent model of depression
Shiromani, P. J., Klemfuss, H., Lucero, S., & Overstreet, D. H. (1991) · Biological Psychiatry · doi:10.1016/0006-3223(91)90059-u · Cited by 33 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Lithium's effects on muscarinic receptor binding parameters: a relationship to therapeutic efficacy?
Dilsaver, S. C. (1984) · PubMed · Cited by 26 · see citing works
Early development of muscarinic supersensitivity in a genetic animal model of depression.
Daws, L. C., Schiller, G. D., Overstreet, D. H., & Orbach, J. (1991) · PubMed · Cited by 25 · see citing works
Neurobiologic effects of bright artificial light
Dilsaver, S. C. (1989) · Brain Research Reviews · doi:10.1016/0165-0173(89)90016-7 · Cited by 24 · see citing works
Enhanced Affective Aggression in Genetically Bred Hypercholinergic Rats
Puciłowski, O., Eichelman, B. S., Overstreet, D. H., Rezvani, A. H., & Janowsky, D. S. (2008) · Neuropsychobiology · doi:10.1159/000119040 · Cited by 24 · see citing works
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 · see citing works
Bright artificial light subsensitizes a central muscarinic mechanism
Dilsaver, S. C., & Majchrzak, M. J. (1987) · Life Sciences · doi:10.1016/0024-3205(87)90274-8 · Cited by 21 · see citing works
Heritability of dark pulse triggering of paradoxical sleep in rats
Leung, C. G., Bergmann, B. M., Rechtschaffen, A., & Benca, R. M. (1992) · Physiology & Behavior · doi:10.1016/0031-9384(92)90441-4 · Cited by 18 · see citing works
Mood Disorders: Toward a New Psychobiology
Paykel, E. S. (1985) · American Journal of Psychiatry · doi:10.1176/ajp.142.9.1113 · Cited by 18 · see citing works
Commentary: A behavioral, psychopharmacological, and neurochemical update on the flinders sensitive line rat, a potential genetic animal model of depression
Overstreet, D. H. (1991) · Behavior Genetics · doi:10.1007/bf01067667 · Cited by 17 · see citing works
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 · see citing works
Effects of bright light on responsiveness to a muscarinic agonist in rats selectively bred for endogenously increased cholinergic function
Overstreet, D. H., Dilsaver, S. C., Janowsky, D. S., & Rezvani, A. H. (1990) · Psychiatry Research · doi:10.1016/0165-1781(90)90068-g · Cited by 15 · see citing works
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 · see citing works
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 · see citing works
The effects of lesions of the locus coeruleus and treatment with drugs affecting brain noradrenergic neurotransmission on dominant-subordinate behavior in rats competing for water.
Plewako, M., & Kostowski, W. (1985) · PubMed · Cited by 14 · see citing works
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 · see citing works
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 · see citing works
Preclinical and clinical studies with corticotropin-releasing factor: implications for affective disorders.
Owens, M. J., & Nemeroff, C. B. (1988) · PubMed · Cited by 11 · see citing works
Bright light blocks amitriptyline-induced cholinoceptor supersensitivity
Dilsaver, S. C., Majchrzak, M. J., & Flemmer, D. D. (1989) · Biological Psychiatry · doi:10.1016/0006-3223(89)90059-0 · Cited by 10 · see citing works
Monoaminergic control of affective aggression.
Puciłowski, O. (1987) · PubMed · Cited by 10 · see citing works
Biochemical and pharmacological evidence for central cholinergic regulation of shock-induced aggression in rats
Ray, A., Sen, P., & Alkondon, M. (1989) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(89)90050-6 · Cited by 8 · see citing works
EFFECTS OF ACUTE AND CHRONIC STRESSORS ON SACCHARIN PREFERENCE IN HYPERCHOLINERGIC RATS
Puciłowski, O., Overstreet, D. H., Rezvani, A. H., & Janowsky, D. S. (1992) · Behavioural Pharmacology · doi:10.1097/00008877-199204001-00151 · Cited by 8 · see citing works
Relation between the thermoregulatory effects of intracerebroventricularly injected dopamine and 5-hydroxytryptamine in the rabbit
de Roij, T. A. J. M., Frens, J., Vianen-Meijerink, M., & Nijnanten, F. M. A. W.-V. (1979) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf00515594 · Cited by 8 · see citing works
Genetic Animal Models of Endogenous Depression
Overstreet, D. H. (1992) · Birkhäuser Boston eBooks · doi:10.1007/978-1-4899-6732-9_12 · Cited by 7 · see citing works
Amitriptyline-induced supersensitivity of a central muscarinic mechanism: Lithium blocks Amitriptyline- induced supersensitivity
Dilsaver, S. C., & Hariharan, M. (1988) · Psychiatry Research · doi:10.1016/0165-1781(88)90049-2 · Cited by 5 · see citing works
Effects of calcium channel inhibitors on the hypothermic response to oxotremorine in normo and hypercholinergic rats
Puciłowski, O., Overstreet, D. H., Rezvani, A. H., & Janowsky, D. S. (1991) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1991.tb03505.x · Cited by 4 · see citing works
Central Control of Anterior Pituitary Function
Arnold, M. A., & Martin, J. B. (1989) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-73551-6_3 · Cited by 3 · see citing works

Flagged first, then by citations

4 of the 170 references couldn’t be matched to a known paper.

Sorted by citations

Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 396 · see citing works
Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression
Drevets, W. C., Price, J. L., & Furey, M. L. (2008) · Brain Structure and Function · doi:10.1007/s00429-008-0189-x · Cited by 2,209 · see citing works
“In a line of rats genetically bred for increased sensitivity of muscarinic receptors, the use of cholinergic agonists results in the enhancement of the behavioral analogs of depression, while the use of antimuscarinic drugs results in the improvement in these behaviors (Overstreet 1993).”
Background
Limbic-cortical dysregulation: a proposed model of depression
(1997) · The Journal of Neuropsychiatry and Clinical Neurosciences · doi:10.1176/jnp.9.3.471 · Cited by 1,585 · see citing works
Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants
Detke, M. J., Rickels, M. R., & Lucki, I. (1995) · Psychopharmacology · doi:10.1007/bf02245592 · Cited by 1,438 · see citing works
“1993) or when given repeatedly for 14 days (Overstreet 1993).”
Background
Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior
Picciotto, M. R., Higley, M. J., & Mineur, Y. S. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.036 · Cited by 1,404 · see citing works
“In rodent studies, the Flinders rat model was selected for its sensitivity to challenge with an AChE inhibitor, and sensitive rats also display a constellation of depression-like endophenotypes, supporting the idea that increasing ACh levels increases symptoms of depression (Overstreet, 1993).”
Background
Neurobiological similarities in depression and drug dependence: a self-medication hypothesis
Markou, A. (1998) · Neuropsychopharmacology · doi:10.1016/s0893-133x(97)00113-9 · Cited by 767 · see citing works
Dopamine system dysregulation in major depressive disorders
Belujon, P., & Grace, A. A. (2017) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx056 · Cited by 754 · see citing works
“It has also been reported that the Flinders sensitive rat line, a genetic animal model of depression (Overstreet, 1993), show reduced “burst” firing of VTA neurons (Friedman et al.”
Background
Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects
Mahar, I., Bambico, F. R., Mechawar, N., & Nobrega, J. N. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.11.009 · Cited by 694 · see citing works
Effect of nicotine and nicotinic receptors on anxiety and depression
Picciotto, M. R., Brunzell, D. H., & Caldarone, B. J. (2002) · Neuroreport · doi:10.1097/00001756-200207020-00006 · Cited by 483 · see citing works
Treatment resistant depression: A multi-scale, systems biology approach
Akil, H., Gordon, J. A., Hen, R., Javitch, J. A., Mayberg, H. S., McEwen, B. S., Meaney, M. J., & Nestler, E. J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.08.019 · Cited by 443 · see citing works
“Another rodent model that has been useful to study depression-related behavior and to screen for antidepressants are the Flinders Sensitive (FSL) and Resistant (FRL) lines (Overstreet, 1993).”
Background
The validity of animal models of predisposition to depression
Willner, P., & Mitchell, P. J. (2002) · Behavioural Pharmacology · doi:10.1097/00008877-200205000-00001 · Cited by 430 · see citing works
Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine: A Randomized, Placebo-Controlled Clinical Trial
Furey, M. L., & Drevets, W. C. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.10.1121 · Cited by 417 · see citing works
“Moreover, rats bred selectively for increased sensitivity of muscarinic receptors showed putative behavioral analogues of depression, such as lethargy, reductions in self-stimulation, and increased behavioral despair, in the forced swim test in response to cholinomimetic drugs.(23,24) Some tricyclic antidepressant (TC…”
Background
The Flinders Sensitive Line rat: A selectively bred putative animal model of depression
Overstreet, D. H., Friedman, E. M., Mathé, A. A., & Yadid, G. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.015 · Cited by 375 · see citing works
Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior
Mineur, Y. S., Obayemi, A., Wigestrand, M. B., Fote, G. M., Calarco, C. A., Li, A. M., & Picciotto, M. R. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1219731110 · Cited by 375 · see citing works
“pha-helical CRF(9-41), reverses nicotine-induced conditioned, but not unconditioned,”
BackgroundResultInfluential
Medial preoptic area interactions with dopamine neural systems in the control of the onset and maintenance of maternal behavior in rats
Numan, M., & Stolzenberg, D. S. (2008) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2008.10.002 · Cited by 361 · see citing works
Nicotinic receptors in the brain. Links between molecular biology and behavior
Picciotto, M. (2000) · Neuropsychopharmacology · doi:10.1016/s0893-133x(99)00146-3 · Cited by 354 · see citing works
“FSL rats, which were selectively bred for increased sensitivity to anticholinesterase agents, have been proposed as an animal model of depression (Overstreet 1993), because they have lower body weight, lower locomotor activity, increased REM learning difficulties, anhedonia when exposed to chronic…”
Background
Animal Models of Depression: Utility for Transgenic Research
Porsolt, R. D. (2000) · Reviews in the Neurosciences · doi:10.1515/revneuro.2000.11.1.53 · Cited by 284 · see citing works
Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis
Mineur, Y. S., & Picciotto, M. R. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.09.004 · Cited by 277 · see citing works
The SEEKING mind: Primal neuro-affective substrates for appetitive incentive states and their pathological dynamics in addictions and depression
Alcaro, A., & Panksepp, J. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.03.002 · Cited by 240 · see citing works
Modeling Depression in Animal Models
Overstreet, D. H. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-458-2_7 · Cited by 236 · see citing works
The antidepressant effect of running is associated with increased hippocampal cell proliferation
Bjørnebekk, A., Mathé, A. A., & Brené, S. (2005) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145705005122 · Cited by 231 · see citing works
“The FSL rats show behavioural and neurochemical similarities to human depression and respond to chronic but not acute treatment with several antidepressants (Overstreet, 1993, 1995 ; Zangen et al., 1997).”
Background
The Flinders Sensitive Line Rat Model of Depression—25 Years and Still Producing
Overstreet, D. H., & Wegener, G. (2013) · Pharmacological Reviews · doi:10.1124/pr.111.005397 · Cited by 228 · see citing works
“Therefore, it had been claimed for many years (e.g., Overstreet, 1993) that the FSL rat was a “pure” animal model of depression.”
BackgroundMethodInfluential
From monoamines to genomic targets: a paradigm shift for drug discovery in depression
Wong, M., & Licinio, J. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1303 · Cited by 225 · see citing works
Chronic mild stress-induced anhedonia: Greater effect in a genetic rat model of depression
Puciłowski, O., Overstreet, D. H., Rezvani, A. H., & Janowsky, D. S. (1993) · Physiology & Behavior · doi:10.1016/0031-9384(93)90351-f · Cited by 216 · see citing works
Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease
Bonaz, B., Sinniger, V., & Pellissier, S. (2017) · Journal of Internal Medicine · doi:10.1111/joim.12611 · Cited by 213 · see citing works
Behavioral effects of neuropeptides in rodent models of depression and anxiety
Rotzinger, S., Lovejoy, D. A., & Tan, L. A. (2010) · Peptides · doi:10.1016/j.peptides.2009.12.015 · Cited by 211 · see citing works
Animal models of depression in drug discovery: A historical perspective
McArthur, R. A., & Borsini, F. (2006) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2006.06.005 · Cited by 209 · see citing works
The Neuropeptide Y (NPY) Y1 Receptor Subtype Mediates NPY-induced Antidepressant-like Activity in the Mouse Forced Swimming Test
Redrobe, J. P. (2002) · Neuropsychopharmacology · doi:10.1016/s0893-133x(01)00403-1 · Cited by 207 · see citing works
“1999), a purported genetic animal model of depression (Overstreet 1993; Overstreet et al. 1995).”
Background
Genetic Contributions to Addiction
Crabbe, J. C. (2002) · Annual Review of Psychology · doi:10.1146/annurev.psych.53.100901.135142 · Cited by 203 · see citing works
The WAG/Rij strain: A genetic animal model of absence epilepsy with comorbidity of depressiony
Sarkisova, K. Y., & van Luijtelaar, G. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.11.010 · Cited by 198 · see citing works
Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility
Nasca, C., Bigio, B., Zelli, D., Nicoletti, F., & McEwen, B. S. (2015) · Molecular Psychiatry · doi:10.1038/mp.2014.96 · Cited by 194 · see citing works
Nicotinic acetylcholine receptors and depression: a review of the preclinical and clinical literature
Philip, N. S., Carpenter, L. L., Tyrka, A. R., & Price, L. H. (2010) · Psychopharmacology · doi:10.1007/s00213-010-1932-6 · Cited by 185 · see citing works
“The theory was given further support by animal studies showing that mice bred specifically for sensitivity to cholinergic agents demonstrated depression-like behaviors (Overstreet 1993).”
High Serotonin and 5‐Hydroxyindoleacetic Acid Levels in Limbic Brain Regions in a Rat Model of Depression; Normalization by Chronic Antidepressant Treatment
Zangen, A., Overstreet, D. H., & Yadid, G. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69062477.x · Cited by 182 · see citing works
The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus
Gulinello, M. E., & Putterman, C. (2011) · BioMed Research International · doi:10.1155/2011/207504 · Cited by 178 · see citing works
“In contrast, animals treated with either pharmacological agents (such as hormones or via depletion of the amino acid tryptophan necessary to make serotonin [99, 100]), environmental manipulations (unpredictable chronic stress, social isolation [101–103]), or genetic alterations (Flinders strain, SERT knockouts [104, 1…”
Background
Association between depressive behavior and absence of serotonin-dopamine interaction in the nucleus accumbens
Zangen, A., Nakash, R., Overstreet, D. H., & Yadid, G. (2001) · Psychopharmacology · doi:10.1007/s002130100746 · Cited by 177 · see citing works
Elucidation of the neurobiology of depression: insights from a novel genetic animal model
Yadid, G., Nakash, R., Roth‐Deri, I., Tamar, G., Kinor, N., Gispan, I. H., & Zangen, A. (2000) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00018-6 · Cited by 171 · see citing works
Effects of chronic mild stress on serum complement activity, saccharin preference, and corticosterone levels in Flinders lines of rats
Ayensu, W. K., Puciłowski, O., Mason, G., Overstreet, D. H., Rezvani, A. H., & Janowsky, D. S. (1995) · Physiology & Behavior · doi:10.1016/0031-9384(94)00204-i · Cited by 171 · see citing works
Circadian rhythms and depression: Human psychopathology and animal models
Kronfeld-Schor, N., & Einat, H. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.020 · Cited by 166 · see citing works
“The Flinders Sensitive Line (FSL) of rats, initially bred for cholinergic hypersensitivity, is repeatedly demonstrated to show a variety of depression-like behaviors (Overstreet, 1993).”
Background
Animal Models of Anxiety
Ohl, F. (2005) · Handbook of experimental pharmacology · doi:10.1007/3-540-28082-0_2 · Cited by 164 · see citing works
“From a number of various findings it was concluded that the Flinders sensitive line, being hypersensitive to cholinergic agonists, may rather represent an animal model of depression more than anxiety disorder, because these rats exhibit several symptom patterns of depression, such as reduced locomotor activity, reduce…”
Background
Dynamics of the dopaminergic system as a key component to the understanding of depression
Yadid, G., & Friedman, A. (2008) · Progress in brain research · doi:10.1016/s0079-6123(08)00913-8 · Cited by 160 · see citing works
Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression
Overstreet, D. H., Puciłowski, O., Rezvani, A. H., & Janowsky, D. S. (1995) · Psychopharmacology · doi:10.1007/bf02245589 · Cited by 161 · see citing works
“Flinders Sensitive Line (FSL) rat, selectively bred for increased cholinergic function (Overstreet 1993), it was”
Influential
Animal models of depression and anxiety: What do they tell us about human condition?
Neumann, I. D., Wegener, G., Homberg, J. R., Cohen, H., Slattery, D. A., Zohar, J., Olivier, J. D. A., & Mathé, A. A. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.11.028 · Cited by 159 · see citing works
“Other classical symptoms of severe depression, decreased appetite and weight loss, are also found in the FSL (Overstreet, 1993, 2002).”
Perspectives for the development of animal models of bipolar disorder
Machado-Vieira, R., Kapczinski, F., & Soares, J. C. (2004) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2003.10.015 · Cited by 158 · see citing works
Long-term changes in open field behaviour following a single social defeat in rats can be reversed by sleep deprivation
Meerlo, P., Overkamp, G. J. F., Benning, M. A., Koolhaas, J. M., & Van Den Hoofdakker, R. H. (1996) · Physiology & Behavior · doi:10.1016/0031-9384(95)02271-6 · Cited by 151 · see citing works
Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior
Friedman, A., Lax, E., Dikshtein, Y., Abraham, L., Flaumenhaft, Y., Sudai, E., Ben‐Tzion, M., Ami-Ad, L., Yaka, R., & Yadid, G. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.06.008 · Cited by 145 · see citing works
“Test duration was 5 minutes (Dremencov et al., 2006; Overstreet, 1993; Overstreet et al., 2005).”
Background
Vmat2 Heterozygous Mutant Mice Display a Depressive-Like Phenotype
Fukui, M., Rodriguiz, R. M., Zhou, J., Jiang, X. “., Phillips, L. E., Caron, M. G., & Wetsel, W. C. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4388-06.2007 · Cited by 147 · see citing works
“In rodents, some animal models of “depression” display anxiety-like responses (Bale et al., 2000; Schramm et al., 2001; Ansorge et al., 2004; Heim et al., 2004; Wei et al., 2004), whereas others do not (Overstreet, 1993).”
BackgroundInfluential
Neuropeptide Y (NPY) and depression: From animal studies to the human condition
Redrobe, J. P., Dumont, Y., & Quirion, R. (2002) · Life Sciences · doi:10.1016/s0024-3205(02)02159-8 · Cited by 146 · see citing works
Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression
Khoury, A. E., Gruber, S. H. M., Mørk, A., & Mathé, A. A. (2006) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2005.11.011 · Cited by 143 · see citing works
Recovering from depression with repetitive transcranial magnetic stimulation (rTMS): a systematic review and meta-analysis of preclinical studies
Risio, L. D., Borgi, M., Pettorruso, M., Miuli, A., Ottomana, A. M., Sociali, A., Martinotti, G., Nicolò, G., Macrı̀, S., Giannantonio, M. D., et al. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-01055-2 · Cited by 139 · see citing works
Is cholinergic sensitivity a genetic marker for the affective disorders?
Janowsky, D. S., Overstreet, D. H., & Nürnberger, J. I. (1994) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320540412 · Cited by 137 · see citing works
Ethopharmacology of imipramine in the forced-swimming test: gender differences
Barros, H. M. T., & Ferigolo, M. (1998) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(98)00029-3 · Cited by 136 · see citing works
The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice
Rabenstein, R. L., Caldarone, B. J., & Picciotto, M. R. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0568-z · Cited by 129 · see citing works
“1998), and the Flinders sensitive line of rats that were bred for cholinergic hypersensitivity are widely used as an animal model of depression (Overstreet 1993).”
ChAT-ChR2-EYFP Mice Have Enhanced Motor Endurance But Show Deficits in Attention and Several Additional Cognitive Domains
Kolisnyk, B., Guzmán-Lenis, M.-S., Raulic, S., Fan, J., Magalhães, A. C., Feng, G., Gros, R., Prado, V. F., & Prado, M. A. M. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0395-13.2013 · Cited by 125 · see citing works
“To note, increased cholinergic transmission has been suggested to be pro-depressive (Janowsky et al., 1972; Overstreet et al., 1986; Overstreet, 1993; Fagergren et al., 2005).”
Background
High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation
Caldarone, B. J., Harrist, A., Cleary, M. A., Beech, R. D., King, S. L., & Picciotto, M. R. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.08.010 · Cited by 122 · see citing works
Lithium treatment alters brain concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a rat model of depression
Angelucci, F., Aloe, L., Jiménez-Vasquez, P., & Mathé, A. A. (2003) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145703003468 · Cited by 157 · see citing works
“Received 6 November 2002 ; Reviewed 29 January 2003 ; Revised 27 February 2003 ; Accepted 9 March 2003 Key words : BDNF, Flinders Sensitive Line rat, GDNF, Lithium, NGF.”
BackgroundResult
Increased catecholamine levels in specific brain regions of a rat model of depression: normalization by chronic antidepressant treatment
Zangen, A., Overstreet, D. H., & Yadid, G. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01214-7 · Cited by 123 · see citing works
Behavioral Characteristics of Rat Lines Selected for Differential Hypothermic Responses to Cholinergic or Serotonergic Agonists
Overstreet, D. H. (2002) · Behavior Genetics · doi:10.1023/a:1020262205227 · Cited by 122 · see citing works
“Details of the selection of these rats have appeared previously ( Overstreet, 1993; Overstreet et al., 1979, 1995, 1998a).”
Background
Effects of chronic antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiologic activity
Grant, M. M., & Weiss, J. M. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(00)00936-7 · Cited by 121 · see citing works
Inverse Correlation of Brain and Blood BDNF Levels in a Genetic Rat Model of Depression
Elfving, B., Plougmann, P. H., Müller, H. K., Mathé, A. A., Rosenberg, R., & Wegener, G. (2010) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709990721 · Cited by 119 · see citing works
“Received 7 July 2009 ; Reviewed 14 August 2009 ; Revised 21 August 2009 ; Accepted 24 August 2009 ; First published online 2 October 2009 Key words : BDNF, blood, correlation, frontal cortex, hippocampus.”
MethodResult
Molecules and circuits involved in nicotine addiction: The many faces of smoking
Picciotto, M. R., & Mineur, Y. S. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.04.028 · Cited by 117 · see citing works
“selecting for vulnerability to a depressive-like response to a cholinesterase antagonist (Overstreet, 1993).”
Background
The kynurenine pathway in major depression: What we know and where to next
Brown, S. J., Huang, X., & Newell, K. A. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.05.018 · Cited by 118 · see citing works
The neurobiological characteristics of rapid eye movement (REM) sleep are candidate endophenotypes of depression, schizophrenia, mental retardation and dementia
Gottesmann, C., & Gottesman, I. I. (2007) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.01.004 · Cited by 114 · see citing works
Antidepressant-like effects of CRF1 receptor antagonist SSR125543 in an animal model of depression
Overstreet, D. H., & Griebel, G. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.06.035 · Cited by 112 · see citing works
“…Line rat is innately more immobile in the forced swim test than its control counterpart, the Flinders Resistant Line rat, and exhibits a decrease in immobility following chronic, but not acute, treatment with desipramine and sertraline (Overstreet, 1993, 2002; Pucilowski and Overstreet, 1993).”
BackgroundMethodInfluential
Selective Breeding of Rats for High and Low Motor Activity in a Swim Test
Weiss, J. M., Cierpial, M. A., & West, C. H. K. (1998) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(98)00075-6 · Cited by 110 · see citing works
Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy
Sarkisova, K. Y., Midzyanovskaya, I. S., & Куликов, М. А. (2003) · Behavioural Brain Research · doi:10.1016/s0166-4328(03)00090-1 · Cited by 109 · see citing works
Alterations in neuropeptide Y and Y1 receptor mRNA expression in brains from an animal model of depression: region specific adaptation after fluoxetine treatment
Caberlotto, L., Fuxé, K., Overstreet, D. H., Gerrard, P. A., & Hurd, Y. L. (1998) · Molecular Brain Research · doi:10.1016/s0169-328x(98)00137-5 · Cited by 107 · see citing works
The catecholaminergic–cholinergic balance hypothesis of bipolar disorder revisited
van Enkhuizen, J., Janowsky, D. S., Olivier, B., Minassian, A., Perry, W., Young, J. W., & Geyer, M. A. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.05.063 · Cited by 106 · see citing works
“Furthermore, this line exhibits depression-like behaviors including lower startle thresholds (Markou et al., 1994), fulfilling some criteria of face, construct, and predictive validities [see (Overstreet, 1993) for review].”
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 · see citing works
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 101 · see citing works
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 103 · see citing works
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 · see citing works
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 99 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 95 · see citing works
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 · see citing works
“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 91 · see citing works
“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 89 · see citing works
“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 86 · see citing works
“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 · see citing works
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 87 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 82 · see citing works
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 · see citing works
“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 · see citing works
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 80 · see citing works
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 79 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 75 · see citing works
“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 · see citing works
“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 75 · see citing works
“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 75 · see citing works
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 · see citing works
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 74 · see citing works
“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 · see citing works

The Flinders Sensitive Line rat: A selectively bred putative animal model of depression
Overstreet, D. H., Friedman, E. M., Mathé, A. A., & Yadid, G. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.015 · Cited by 375 · see citing works
Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression
Overstreet, D. H., Puciłowski, O., Rezvani, A. H., & Janowsky, D. S. (1995) · Psychopharmacology · doi:10.1007/bf02245589 · Cited by 161 · see citing works
Genetic Animal Model of Depression with Cholinergic Supersensitivity
Overstreet, D. H. (1989) · Springer eBooks · doi:10.1007/978-1-4612-3524-8_14 · Cited by 4 · see citing works
The Flinders Sensitive Line Rat Model of Depression—25 Years and Still Producing
Overstreet, D. H., & Wegener, G. (2013) · Pharmacological Reviews · doi:10.1124/pr.111.005397 · Cited by 228 · see citing works
Behavioral characterization of a rat model of depression.
Demers, M. J. (2006) · Digital WPI

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 › 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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