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

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 beta-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 beta-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 beta-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 beta-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.