Are Wistar-Kyoto rats a genetic animal model of depression resistant to antidepressants?
Introduction
The forced swimming test was initially described by Porsolt et al., 1977a, Porsolt et al., 1977b, Porsolt et al., 1978afor the screening of antidepressant drugs and was called the behavioral despair test. Several authors interpret the concept coined by Porsolt et al. as similar to learned helplessness (for instance, see O'Neill and Valentino, 1982), and therefore the test has been considered as a putative animal model of depression (Willner, 1984). However, this interpretation was not suggested by Porsolt (1981)and it is probably not appropriate in that exposure to forced swimming does not cause generalized helplessness in rodents, but only modifies the active behavior of animals when further exposed to a similar situation. In the last decade considerable effort has been made to study the actual meaning of the behavior of the animals in the test and two main hypotheses have been elaborated. One considers that the active behavior of animals in the forced swimming test is a panic-like reaction (Borsini et al., 1986; Nishimura et al., 1988, Nishimura et al., 1989), and the other assumes that the test measures the tendency of the animals to adopt active or passive strategies when faced with stressful inescapable situations (Armario et al., 1988; Martı́ and Armario, 1993). Since the reluctancy to persevere in active behavior when faced with stressful situations might be a component of human depression, the forced swimming test is currently used to relate the immobility of the animals in the test to depressive-like states (Weiss et al., 1981; Garcı́a-Marquez and Armario, 1987a, Garcı́a-Marquez and Armario, 1987b; Paré, 1989a, Paré, 1989b). In fact, a positive correlation between the clinical effectiveness of antidepressants and their potency on forced swimming test behavior has been found (Willner, 1984).
Wistar-Kyoto rats have been reported to display low levels of activity in the forced swimming test and high levels of immobility as compared to either normal outbred Sprague-Dawley rats or several inbred strains, including Spontaneously Hypertensive rats (Paré, 1989a, Paré, 1989b, Paré, 1992; Armario et al., 1995; Lahmame and Armario, 1996; Martı́ and Armario, 1996). Very recently we have also found that among the five inbred strains of rats studied (Brown Norway, Fisher-344, Lewis, Spontaneously Hypertensive rats and Wistar-Kyoto rats), both Spontaneously Hypertensive and Wistar-Kyoto rats, which are genetically close, failed to respond to acute standard doses of desipramine and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in terms of enhanced active behavior in the forced swimming test (Lahmame and Armario, 1996). Apparently these strains are rather insensitive to acute antidepressant administration, a finding that has been also reported for outbred rats from different sources (Porsolt et al., 1978b) and for inbred strains of mice in the forced swimming test or similar animal models of depression (Van der Heyden et al., 1987; Trullas et al., 1989).
The lack of appropriate response to acute antidepressant administration is reminiscent of the delayed response of depressed patients to antidepressants in that these drugs have to be administered chronically to be therapeutically effective. Since there is no animal model of resistance to antidepressants, it was considered of interest to study whether rats of a strain that do not respond to acute standard doses of antidepressants do respond to chronic treatment. At present this finding has been reported for Flinders sensitive line rats, which showed both low levels of active behavior in the forced swimming test and a positive response to chronic but not acute imipramine administration (Schiller et al., 1992). However, in this case no other variable was studied in order to demonstrate that the lack of responsiveness to antidepressants affected the forced swimming test only and that pharmacokinetic factors were not involved.
To circumvent these problems, we studied in the present experiment the influence of acute and chronic imipramine administration on forced swimming test behavior. In order to know whether or not the lower behavioral responsiveness to imipramine was linked to some adaptative neurochemical response to antidepressants, we investigated 5-HT1 and 5-HT2 receptors and β-adrenoceptors, the two latter types having been reported to be down-regulated in response to a wide range of antidepressants, including imipramine (Banerjee et al., 1977; Peroutka and Snyder, 1980; Charney et al., 1981; Zifa and Fillion, 1992; Burnet et al., 1994). In addition, for appropriate interpretation of the forced swimming test behavior we measured: (i) serum imipramine concentration, which might provide information about drug metabolism and (ii) the anorexia caused by imipramine (Broitman and Donoso, 1978; Blavet and Defeudis, 1982) to include another physiological index of the action of the drug.
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Animals
Male Brown Norway, Wistar-Kyoto and Sprague-Dawley rats approximately 40–45 days old upon their arrival at the laboratory were used. They were obtained from Charles River. The rats were housed (two per cage) in a controlled environment (lights on from 07.30 to 19.30 h, temperature 22°C) for at least 10 days before starting the experiments. Food and water were always provided ad libitum.
General procedure
The experimental procedures used in this work were previously approved by the ethics committee for animal
Effects of both acute and chronic imipramine treatment on forced swimming test behavior
Both initial and final body weight for the 3 strains are indicated in Table 1. Forced swimming test behavior is illustrated in Fig. 1. The two-way ANOVA revealed a significant effect of strain (F(2,56)=26.0, P<0.001) and drug treatment (F(2,56)=79.2, P<0.001) on struggling. The interaction was also significant (F(4,56)=4.2, P<0.01). Post-hoc pairwise comparison showed that Wistar-Kyoto rats displayed lower levels of struggling than the other two strains (Student–Newman–Keuls test). Within each
Discussion
It was found, in accordance with previous results, that Wistar-Kyoto rats showed low levels of active behavior (struggling) in the forced swimming test compared to other outbred or inbred strains (Paré, 1989a, Paré, 1989b, Paré, 1992; Armario et al., 1995; Lahmame and Armario, 1996; Martı́ and Armario, 1996). The behavior of the rats in the forced swimming test has been interpreted in two different ways: (i) active behavior (struggling) might be a reflection of a panic-like reaction as a
Acknowledgements
This work was supported by grants DGICYT PM92-0854 and CIRIT GTQ93-2.096. A.L. is a recipient of a grant from the ``Ministerio de Asuntos Exteriores: Agencia Española de Cooperación Internacional''. We thank Pilar Parra (Area d'Investigació Farmacològica, Fundació de Gestió Sanitaria de l'Hospital de la Santa Creu i Sant Pau) for their contribution to imipramine assay and CIBA for the generous gift of imipramine.
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2020, NeuroscienceCitation Excerpt :Wistar-Kyoto (WKY) rats, for example, initially used as the normotensive control strain for the spontaneously hypertensive rat (SHR), exhibit behavioral and physiological abnormalities thought to reflect characteristics of TRD (Willner and Belzung, 2015). Some of these include heightened learned helplessness and social avoidance (Nam et al., 2014), increased vulnerability to the physiological effects of stress (Morilak et al., 2005), apparent subsensitivities to various antidepressant drugs (Lahmame et al., 1997), but responsitivity to ketamine administration (Willner et al., 2019). Yet, little is known regarding the innate oscillatory signatures in these animals that may reflect these behaviors, nor the impact of antidepressant administration on these patterns.