The Forced Swim Test

Behavioral alterations induced by stressful experiences frequently include increased anxiety-related behavior. Accordingly, anxiety has been hypothesized to play a role in stress-coping behavior (Ferre et al. 1994). The most regularly used tests for stress-coping behavior is the so-called forced swim test, which has been developed by Porsolt et al. (1977) as a behavioral paradigm to identify compounds with antidepressant efficacy in humans Mice or rats are forced to 

The Modified Hoie Board Assessing Dimensions of Behavior 

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Skrebuhhova, T., Allikmets, L. Matto, V. (1999). 5-HT2A receptors mediate the effects of antidepressants in the elevated plus-maze test but have a partial role in the forced swim test. Med. Sci. Res., 27, 277-80. 

Zhang ZQ, Li Y, Ming Y, Luo ZP, Zhao YM. The effect of Morinda officinalis How, a Chinese traditional medicinal plant, on the DRL 72-s schedule in rats and the forced swimming test in mice. Pharmacol Biochem Behav 2002 72 39-43. 

Antidepressant Some animal models show antidepressant effects of lobelia extract (Subarnas et al. 1992). Similar to imipramine and mianserin, beta-amyrin palmitate shows antidepressant-like effects in the forced-swimming test (Subarnas et al. 1993a). Whereas mianserin and beta-amyrin palmitate reduce locomotor activity induced by methamphetamine, imipramine increases it. It potentiates sodium pentobarbital-induced sleep more potently than imipramine, but less than mianserin. Collectively, the effects of beta-amyrin palmitate in behavioral and physiological assays suggests it may work in a manner more similar to mianserin than imipramine. However, the mechanism of antidepressant-like effects of lobelia is uncertain. It may be through the beta-amyrin palmitate s ability to release norepinephrine (Subarnas et al. 1993b). An antidepressant effect of lobelia has not been established in humans. 

Antidepressant effects Hypericum has been shown to have antidepressant effects in several animal models. An extract fraction high in naphthodianthrones showed antidepressant effects in the forced-swim test, and was attenuated by a dopamine antagonist (sulpiride) (Butterweck et... 

Subarnas A, Tadano T, Nakahata N, Aral Y, Kinemuchi H, Oshima Y, Kisara K, Ohizumi Y. (1993b). A possible mechanism of antidepressant activity of beta-amyrin palmitate isolated from Lobelia inflata leaves In the forced swimming test. Life Sci. 52(3) 289-96. 

Wieland S, Lucki I. (1990). Antidepressant-like activity of 5-HTlA agonists measured with the forced swim test. Psychopharmacology (Berlin). 101 4497-504. 

Mannucd C, Tedesco M, BeUomo M, Caputi AP, Calapai G (2006) Long-term effects of nicotine on the forced swimming test in mice an experimental model for the study of depression caused by smoke. Neurochem Int 49 481 86... 

Unpredictability also is a central feature in the concept of learned helplessness. This concept, using uncontrollable shock, was introduced by Overmier and Seligman (1967) and is based on the observation that animals exposed to an invariable stressor such as electric foot shock, which, due to the experimental set-up, is uncontrollable in nature, developed behavioral deficits. As first shown by Weiss (1968), rats exposed to uncontrollable shock showed significant weight loss due to decreased food and water intake. Moreover, these animals spent more time immobile in the forced swim test, and they revealed altered sleep patterns as well as a weakened response to previously rewarding brain stimulation, i.e., anhedonia (Henn et al. 1985 Weiss 1991). Importantly, these changes are not seen in animals that receive the same shocks but can exert control over their duration. 

West PA (1990) Neimobehavioral studies of forced swimming. The role of learning and memory in the forced swim test ProgNeimopsychopharmacol Biol Psychiatry 14 863-875 WUlner P (1997) Validity, reliability and utility of the chronic mild stress model of depression a 10-year review and evaluation. Psychopharmacology (Berl) 134 319-329 WUlner P, Muscat R, Papp M (1992) Chronic mUd stress-induced anhedonia a realistic animal model of depression. Neimosci Biobehav Rev 16 525-534 WUson JH (2000) A conspecific attenuates prolactin responses to open-field exposure in rats. Horm Behav 38 39-43... 

In the forced-swimming test, active escape periods alternated with periods in which the animals were completely inactive, or made only the movements necessary to keep their head above water. Tacl mice were more active in this test than animals they spent less time in immobihty. These animals... 

In humans, the antidepressant activity of NMDA receptor antagonists has not been evaluated extensively (Skohiick 1999). In animal models of depression, NMDA receptor antagonists have been reported to exert positive effects in most studies (Trullas 1997). This concerns mainly the forced swim test (Maj 1992 Moryl et al. 1993 PrzegaUnski et al. 1997) and stress-induced anhe-donia (Papp and Moryl 1994). Amantadine but not memantine was effective against reserpine-induced hypothermia (Moryl et al. 1993). In the forced swim test, both amino-adamantanes produced specific antidepressive-like activity (Moryl et al. 1993). 

Stogner KA, Holmes PV (2000) Neuropeptide-Y exerts antidepressant-like effects in the forced swim test in rats. Eur J Pharmacol 387 R9-R10 Stout SC, Owens MJ, Nemeroff CB (2002) Regulation of corticotropin-releasing factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment. J Pharmacol Exp Ther 300 1085-1092 StrOhle A, Jahn H, Montkowski A, Liebsch G, Boll E, Landgraf R, Holsboer F, Wiedemann K (1997) Central and peripheral administration of atriopeptin is anxiolytic in rats. Neuroendocrinology 65 210-215... 

Animal behavioral models can be used to evaluate the effect of antidepressants on depression [Thiebot et al. 1992]. If TMS and ECT exert antidepressant effects by a similar mechanism, animal models for depression that are sensitive to electroconvulsive shock [ECS] should also be sensitive to TMS. ECS has effects on known animal models for depression. These effects may be displayed after recovery from the immediate effects of the convulsions [Thiebot et al. 1992]. We evaluated the effects of TMS on the forced swimming test and on apomorphine-induced stereotypy, a sensitive behavioral measure for the effects of repeated ECS. 

The forced swimming test model of depression is based on the hypothesis that the animal has lost the ability to escape an aversive situation [Thiebot et al. 1992]. Rats swim in a restricted area and after unsuccessful attempts to escape become gradually immobile [Porsolt et al. 1979]. The swimming-induced immobility is attenuated by most antidepressants [Thiebot et al. 1992], including ECS [Borsini and Meli 1988 Czyrak 1993 Kawashima et al. 1987]. 

Borsini F, Meli A Is the forced swimming test a suitable model for revealing antidepressant activity Psychopharmacology 94 147-160, 1988 Borsini F, Lecci A, Mancinelli A, et al Stimulation of dopamine D2 but not Dj receptors reduces immobility time of rats in the forced swimming test implication for antidepressant activity. Eur J Pharmacol 148 301-307, 1988 Bouchard JM, Delaunay J, Delisle J-P, et al Citalopram versus maprotiline a controlled clinical multicenter trial in depressed patients. Acta Psychiatr Scand 76 583-592, 1987... 

Cervo L, Rossi C, Samanin R The role of serotonin and dopamine in brain in the antidepressant-like effect of clonidine in the forced swimming test. Neuropharmacology 31 331-335, 1992... 

Cummings JL, Miller B, Hill MA, et al Neuropsychiatric aspects of multi-infarct dementia and dementia of the Alzheimer type. Arch Neurol 44 389-393, 1987 Cundall RL, Brooks PW, Murray LG A controlled evaluation of lithium prophylaxis in affective disorders. Psychol Med 2 308-311, 1972 Cutler NR, Haxy J, Kay AD, et al Evaluation of zimeldine in Alzheimer s disease cognitive and biochemical measures. Arch Neurol 42 744-748, 1985 Czyrak A The effect of chronic nifedipine and ECS in the forced swimming test in rats. PolJ Pharmacol 45 191-195, 1993... 

Imperato A, Obinu MC, Cabib S, et al Effects of subchronic minaprine on dopamine release in the ventral striatum and on immobility in the forced swimming test. Neurosci Lett 166 69-72, 1994... 

Maj J, Rogoz Z, Skuza G, et al Antidepressants given repeatedly increase the behavioural effect of dopamine D2 agonist. J Neural Transm 78 1-8, 1989 Maj J, Rogoz Z, Skuza G The effect of combined treatment with MK-801 and antidepressant drugs in the forced swimming test in rats. Polish Journal of Pharmacology and Pharmacy 44 217-226, 1992... 

Although somewhat outside the scope of this text, a non-pharmacological treatment that may become an important therapeutic tool in the future deserves to be mentioned within this outlook section. Initial clinical data indicate that depressive patients are significantly improved after TMS treatment and the procedure is very well tolerated (Berman et til., 2000 McNamara et ul.. 2001). Interestingly for preclinical research, repeated TMS in rats has also been shown to have an antidepressant-like effect (Sachdev et ul., 2002) in the forced swim test described later in this chapter. Whether or not there are psychopharmacological correlates of TMS is unknown at present. 

Sachdev, P.S., McBride, R., Loo, C. Effects of different frequencies of transcranial magnetic stimulation (TMS) on the forced swim test model of depression in rats. Biol. Psychiatry 15, 474-179, 2002. 

Preliminary results from case reports, case series, and open and increasingly better controlled trials have found TMS to be effective in the treatment of depression. TMS, antidepressants, and ECS appear to induce similar effects in animal behavioral models of depression and changes in brain neurochemical activity. These include changes in the forced swim test, increase in seizure threshold, and effects on b-noradrenergic receptor downregulation. Whereas seizures appear unnecessary to achieve clinical benefit with TMS, it is still unclear what aspects are beneficial. As noted earlier, although this modality is associated with some complications (e.g., headaches and, rarely, inadvertent seizure) relative to ECT and perhaps even pharmacotherapy under certain situations, it appears to be quite safe. Future studies of major depression should explore TMS-related issues such as the following ... 

Butterweck V, Petereit F, Winterhoff H, Nahrstedt A. Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test. Planta Med 1998 64 291-294. 

Noeldner M, Schotz K. Rutin is essential for the antidepressant activity of Hypericum perforatum extracts in the forced swimming test. Planta Med 2002 68 577-580. 

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