Abstract
Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these “therapeutic” effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond “therapeutically” to antidepressants and not psychomotor stimulants.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Abel EL (1991) Behavior and corticosteroid response of Maudsley reactive and nonreactive rats in the open field and forced swimming tests. Physiol Behav 50:151–155
Adlersberg S, Toren P, Mester R, Rehavi M, Skolnick P, Weizman A (1994) Verapamil is not an antidepressant in patients resistant to tricyclic antidepressants. Clin Pharmacol 17:294–297
Affolter H, Erne P, Burgisser E, Pletscher A (1984) Calcium as messenger of 5-HT-2 receptor stimulation in human blood platelets. Naunyn-Schmiedeberg's Arch Pharmacol 325:337–342
Anisman HA, Zacharko RM (1982) Depression. The predisposing influence of stress. Behav Brain Sci 5:89–137
Arora RC, Tong C, Jackman H, Stoff D, Meltzer HY (1983) Serotonin uptake and imipramine binding in blood platelets and brain of Fawn-Hooded and Sprague-Dawley rats. Life Sci 33:437–442
Aulakh CS, Wozniak KM, Hill JL, DeVane CL, Tolliver TJ, Murphy DL (1988) Differential neuroendocrine responses to the 5-HT agonistm-chlorophenylpiperazine in Fawn-Hooded rats relative to Wistar and Sprague-Dawley rats. Neuroendocrinology 48:401–406
Beardslee SL, Papadakis E, Altman HJ, Harrington GM, Commissaris RL (1989) Defensive burying in Maudsley reactive (MR/Har) and nonreactive (MNR/Har) rats. Physiol Behav 45:449–451
Berrettini WH, Harris N, Ferraro TN, Vogel WH (1994) Maudsley reactive and non-reactive rats differ in exploratory behavior but not in learning. Psychiatr Genet 4:91–94
Bidzinski A, Jankowska E, Pucilowski O (1990) Antidepressant-like action of nicardipine, verapamil and hemicholinium-3 injected into the anterior hypothalamus in the forced swim test. Pharmacol Biochem Behav 36:795–798
Blackshear A, Friedman RL, Sanders-Bush E (1983) Acute and chronic effects of serotonin antagonists on serotonin binding sites. Naunyn Schmiedeberg's Arch Pharmacol 324:125–129
Blizard DA (1981) The Maudsley reactive and nonreactive strains: a North American perspective. Behav Genet 11:469–489
Borsini F, Meli A (1988) Is the forced swim test a suitable model for revealing antidepressant activity? Psychopharmacology 94:147–160
Braff DL, Geyer MA (1990) Sensorimotor gating and schizophrenia: human and animal model studies. Arch Gen Psychiatry 47:181–188
Bushnell PJ, Padilla S, Ward T, Pope CN, Olszyk VB (1991) Behavioral and neurochemical changes in rats dosed repeatedly with diisopropylfluorophosphate. J Pharmacol Exp Ther 256:741–750
Bushnell PJ, Levin ED, Overstreet DH (1995) Spatial working and reference memory in rats bred for autonomic sensitivity to cholinergic stimulation: acquisition, accuracy, speed, and effects of cholinergic drugs. Neurobiol Learn Mem 63:116–132
Casebolt TL, Jope RS (1989) Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain. Biol Psychiatry 25:329–340
Cervo L, Grignaschi G, Rossi C, Samanin (1991) Role of serotonergic neurons in the effects of sertraline in rats in the forced swimming test. Eur J Pharmacol 196:217–222
Chippendale TJ, Zawolkow GA, Russell RW, Overstreet DH (1972) Tolerance to low acetylcholinesterase levels: modification of behavior without acute behavioral change. Psychopharmacologia 20:32–41
Crocker AD, Overstreet DH (1991) Changes in dopamine sensitivity in rats selectively bred for differences in cholinergic function. Pharmacol Biochem Behav 38: 105–108
Curzon G, Kennett GA, Sarnia GA, Whitton PS (1992) The effects of tianeptine and other antidepressants on a rat model of depression. Br J Psychiatry 160 [suppl. 15]: 51–55
Detke MJ, Wieland S, Lucki I (1995) blockade of the antidepressant-like effects of 8-OH-DPAT, buspirone and desipramine in the rat forced swim test by 5-HT-1A receptor antagonists. Psychopharmacology 119: 41–54
Dilsaver SC (1989) Neurobiologic effects of bright light. Brain Res Rev 14: 311–334
Dilsaver SC, Greden JF (1984a) Antidepressant withdrawal phenomena. Biol Psychiatry 19: 237–256
Dilsaver SC, Greden JF (1984b) Antidepressant withdrawal-induced activation (hypomania and mania): mechanism and theoretical significance. Brain Res Rev 7: 29–48
Dubovsky SL (1993) Calcium antagonists in manic-depressive illness. Neuropsychobiology 27: 186–192
Fernandez-Teruel A, Boix F, Escorinhuela RM, Guix T, Tobena A (1989) Activity of several GABAergic agents on the behavioral “despair” test in rats. Psychiatr Psychobiol 4 167–173
Goodwin FK, Jamison KR (1990) Manic-depressive illness Oxford University Press, New York, p 567
Goodwin FK, Murphy DL, Dunner DL, Bunney WE Jr (1972) Lithium response in unipolar versus bipolar depression Am J Psychiatry 129: 44–47
Goodwin GH, Green AR, Johanson P (1984) 5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated headtwitch behavior following antidepressant treatment to mice. Br J Pharmacol 83: 235–242
Green AR, DeSouza RJ, Davies EM, Cross AJ (1990) The effects of calcium antagonists and hydralazine on central 5-hydroxytryptamine biochemistry and function in rats and mice. Br J Pharmacol 99: 41–46
Heninger GR, Charney DS, Sternberg DE (1983) Lithium carbonate augmentation of antidepressant treatment: an effective prescription for treatment-refractory depression. Arch Gen Psychiatry 40: 1335–1342
Hoschl C (1991) Do calcium antagonists have a place in the treatment of mood disorders? Drugs 42: 721–729
Janowsky DS, Risch SC (1987) Acetylcholine mechanisms in affective disorders. In: Meltzer HY (ed) Psychopharmacology. The third generation of progress. Raven Press, New York, pp 527–534
Janowsky DS, Overstreet DH, Nurnberger JI Jr (1994) Is cholinergic sensitivity a genetic marker for the affective disorders? Am J Med Genet [Neuropsychiatric Genetics] 54: 335–344
Jope RS, Morrisett RA, Snead OC (1986) Characterization of lithium potentiation of pilocarpine-induced status epilepticus in rats. Exp Neurol 91: 471–480
Kelly JP, Leonard BE (1994) The effects of tianeptine and sertraline in three animal models of depression. Neuropharmacology 33: 1011–1016
Kiowski W, Buhler FR, Fadyomi M, Erne P, Muller FB, Hulthen UL, Bolli P (1986) Age, race, blood pressure and renin: predictions for antihypertensive treatment with calcium antagonists. Am J Cardiol 56: 81H-85H
Kripke DF, Mullaney DJ, Klauber MR, Risch SC, Gillin JC (1992) Controlled trial of bright light for nonseasonal major depressive disorders. Biol Psychiatry 31: 119–134
Kusumi I, Koyama T, Yamashita T (1991) Serotonin-stimulated calcium response is increased in the blood platelets of depressed patients. Biol Psychiatry 30: 310–312
Markou A, Matthews K, Overstreet DH, Koob GF, Geyer MA (1994) Flinders resistant hypocholinergic rats exhibit startle sensitization and reduced startle thresholds. Biol Psychiatry 36: 680–688
Martin P, Laurent S, Massol J, Childs M, Puech AJ (1989) Effects of dihydropyridine drugs on reversal by imipramine on a learned helplessness paradigm in rats. Eur J Pharmacol 162: 185–188
Muller P, Seeman P (1977) Brain neurotransmitter receptors after long-term haloperidol — dopamine, acetylcholine, serotonin, alpha-noradrenergic and naloxone receptors. Life Sci 21: 1751–1758
Nemeroff CB (1994) Evolutionary trends in the pharmacotherapeutic management of depression. J Clin Psychiatry 55 [Suppl Dec]: 3–15
O'Donnell JM, Seiden LS (1983) Differential-reinforcement-of-low rat 72-second schedule: selective effects of antidepressant drugs. J Pharmacol Exp Ther 224: 80–88
Overstreet DH (1986) Selective breeding for increased cholinergic function: development of a new animal model of depression. Biol Psychiatry 21: 49–58
Overstreet DH (1993) The Flinders Sensitive Line rats: a genetic animal model of depression. Neurosci Biobehav Rev 17: 51–68
Overstreet DH, Russell RW (1982) Selective breeding for sensitivity to DFP. Effects of cholinergic agonists and antagonists. Psychopharmacology. 78: 150–154
Overstreet DH, Russell RW, Crocker AD, Schiller GD (1984) Selective breeding for differences in cholinergic function: pre- and post-synaptic mechanisms involved in sensitivity to the anticholinesterase, DFP. Brain Res 294: 327–332
Overstreet DH, Janowsky DS, Gillin JC, Shiromani P, Sutin EL (1986) Stress-induced immobility in rats with cholinergic supersensitivity. Biol Psychiatry. 21: 657–664
Overstreet DH, Russell RW, Crocker AD, Gillin JC, Janowsky DS (1988) Genetic and pharmacological models of cholinergic supersensitivity and affective disorders. Experientia 44: 465–472
Overstreet DH, Double K, Schiller GD (1989a) Antidepressant effects of rolipram in a genetic animal model of depression: cholinergic supersensitivity and weight gain. Pharmacol Biochem Behav 34: 691–696
Overstreet DH, Janowsky DS, Rezvani AH (1989b) Alcoholism and depressive disorders: is cholinergic sensitivity a biological marker? Alcohol Alcohol 24: 253–255
Overstreet DH, Dilsaver SC, Janowsky DS, Rezvani AH (1990) Effects of bright light on responsiveness to a muscarinic agonist in rats selectively bred for endogenously increased cholinergic function. Psychiatry Res 33: 139–150
Overstreet DH, Rezvani AH, Janowsky DS (1992a) Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism. Biol Psychiatry 31: 919–936
Overstreet DH, Rezvani AH, Janowsky DS (1992b) Maudsley reactive and nonreactive rats differ only in some tasks reflecting emotionality. Physiol Behav 52: 149–152
Overstreet DH, Rezvani AH, Pucilowski O, Gause L, Janowsky DS (1994a) Rapid selection for serotonin-1A sensitivity in rats. Psychiatr Genet 4: 57–62
Overstreet DH, Janowsky DS, Pucilowski O, Rezvani AH (1994b) Swim test immobility cosegregates with serotonergic but not cholinergic sensitivity in cross breeds of Flinders Line rats. Psychiatr Genet 4: 101–107
Overstreet DH, Janowsky DS, Pucilowski O, Rezvani AH (1994c) Behavioral correlates of selective breeding for serotonin-1A receptor sensitivity. Neuropsychopharmacology 10: 174–227
Pellow S, Chopin P, File SE, Briley M (1985) Validation of openclosed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Meth 14: 149–167
Pepe S, Overstreet DH, Crocker AD (1988) Enhanced benzodiazepine responsiveness in rats with increased cholinergic function. Pharmacol Biochem Behav. 31: 15–20
Peroutka SJ, Snyder SH (1980) Long-term antidepressant treatment decreases spiroperidol-labelled serotonin receptor binding. Science 210: 86–90
Porsolt RD, Anton G, Blavet N, Jalfre M (1977) Behavioral despair in rats: a new model sensitive to anti-depressant treatments. Eur J Pharmacol 47: 379–391
Pucilowski O (1992) Psychopharmacological properties of calcium channel inhibitors. Psychopharmacology 109: 12–29
Pucilowski O, Overstreet DH (1993) Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains. Pharmacol Biochem Behav 32: 471–475
Pucilowski O, Overstreet DH, Rezvani AH, Janowsky DS (1993) Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression. Physiol Behav 54: 1215–1220
Raftery EB (1984) Cardiovascular drug withdrawal syndromes. A potential problem with calcium antagonists? Drugs 28: 371–374
Richardson JS (1991) The olfactory bulbectomized rat as a model of major depressive disorder. In Boulton AA, Baker GB, Martin-Iverson MT (ed) Neuromethods 19. Animal models in Psychiatry, II. Humana Press, Clifton, NJ, pp 61–79
Rowntree DW, Neven S, Wilson A (1950) The effect of diisopropylfluorophosphonate in schizophrenia and manic depressive psychosis. J Neurol Neurosurg Psychiatry 13: 47–62
Russell RW, Overstreet DH (1987) Mechanisms underlying sensitivity to organophosphorus anticholinesterase agents. Prog Neurobiol. 28: 97–129
Schiller GD, Daws LC, Overstreet DH, Orbach J (1991) Absence of anxiety in an animal model of depression with cholinergic supersensitivity. Brain Res Bull 26: 443–447
Schiller GD, Pucilowski O, Wienicke C, Overstreet DH (1992) Immobility-reducing effect of antidepressants in a genetic animal model of depression. Brain Res Bull 28: 821–823
Schopf J (1989) Treatment of depressions resistant to tricyclic antidepressants, related drugs or MAO inhibitors by lithium addition: review of the literature. Pharmacopsychiatry 22: 174–182
Shiromani PJ, Overstreet DH, Levy D, Goodrich CA, Campbell SS, Gillin JC (1988) Increased REM sleep in rats selectively bred for cholinergic hyperactivity. Neuropsychopharmacology 1: 127–133
Shiromani PJ, Overstreet DH, Lucero S, Double KL, Jeong DO (1990a) Dietary lithium blunts oxotremorine-induced hypothermia in a genetic animal model of depression. Lithium 1: 186–190
Shiromani PJ, Overstreet DH, Lucero S (1990b) Failure of dietary lithium to alter immobility in an animal model of depression. Lithium 1: 241–244
Swerdlow NR, Caine SB, Geyer MA (1992) Regionally selective effects of intracerebral dopamine infusion on sensorimotor gating of the startle reflex in rats. Psychopharmacology 108: 189–195
Tandon R, Greden JF (1989) Cholinergic hyperactivity and negative schizophrenic symptoms: a model of dopaminergic/cholinergic interactions in schizophrenia. Arch Gen Psychiatry 46: 745–753
Thiebot MH, Martin P, Puech AJ (1992) Animal behavioural studies in the evaluation of antidepressant drugs. Br J Psychiatry 160 [Suppl. 15]: 44–50
vanRiezen H, Leonard BE (1992) Effects of psychotropic drugs in the behavior and neurochemistry of olfactory bulbectomized rats. Pharmacol Ther 47: 21–34
Vetulani J (1993) The action of antidepressant drugs administered during calcium channel blockade. Pol J Pharmacol 45: 179–184
Wallis E, Overstreet DH, Crocker AD (1988) Selective breeding for increased cholinergic function: increased serotonergic sensitivity. Pharmacol Biochem Behav 31: 345–350
Willner P (1984) The validity of animal models of depression. Psychopharmacology 83: 1–16
Willner P (1990) Animal models of depression: an overview. Pharmacol Ther 45: 425–455
Willner P (1991) Animal models as simulations of depression. Trends Pharmacol Sci 12: 131–136
Willner P, Muscat R, Papp M (1993) Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 16: 525–534
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Overstreet, D.H., Pucilowski, O., Rezvani, A.H. et al. Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression. Psychopharmacology 121, 27–37 (1995). https://doi.org/10.1007/BF02245589
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02245589