Are Wistar-Kyoto rats a genetic animal model of depression resistant to antidepressants?

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Abstract

Wistar-Kyoto rats are reported to be very passive in the forced swimming test. In addition, they did not respond to acute administration of either desipramine or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In the present experiment, it was studied whether or not they respond to acute and chronic administration of imipramine and the possible relationship to down-regulation of β-adrenoceptors and 5-HT1 and 5-HT2 receptors. Sprague-Dawley and Brown–Norway rats were included in the study as it has been previously demonstrated that the two strains respond to acute desipramine and 8-OH-DPAT administration. Whereas acute administration of imipramine (15 mg/kg, three times in a 24 h period) significantly increased struggling and reduced immobility in Sprague-Dawley and Brown Norway rats, Wistar-Kyoto rats failed to respond to the drug. After chronic treatment with imipramine (13 days plus the acute imipramine treatment at the end of the treatment period), the three strains showed a positive response that was always significantly greater than the response to acute administration, but which was much lower in Wistar-Kyoto than in the other two strains. Down-regulation of both β-adrenoceptors and 5-HT2 receptors was observed 24 h after the forced swimming test in acutely and chronically imipramine-treated rats of the three strains, except that in Sprague-Dawley rats β-adrenoceptors did not change after acute imipramine. No significant decrease in 5-HT1 binding sites was observed in any strain. Acute imipramine administration caused a similar anorexia in Wistar-Kyoto as in the other strains and at least the same level of down-regulation of β-adrenoceptors and 5-HT2 receptors. In addition, serum imipramine levels on the day after the last drug administration were higher in Wistar-Kyoto than in the other two strains. All these data suggest that the subsensitivity to imipramine observed in Wistar-Kyoto rats: (i) can not be primarily explained by pharmacokinetic differences, and (ii) does not appear to be related to the monoaminergic systems. Wistar-Kyoto rats might be therefore not only a good animal model of depressive-like (passive) behavior, but also a model of resistance to antidepressants which could be used to investigate the neurobiological basis of such resistance, which is also observed in some depressed patients.

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.

Section snippets

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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