A. Lahmame et al., ARE WISTAR-KYOTO RATS A GENETIC ANIMAL-MODEL OF DEPRESSION RESISTANT TO ANTIDEPRESSANTS, European journal of pharmacology, 337(2-3), 1997, pp. 115-123
Wistar-Kyoto rats are reported to be very passive in the forced swimmi
ng test. In addition, they did not respond to acute administration of
either desipramine or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPA
T). In the present experiment, it was studied whether or not they resp
ond 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 acu
te administration of imipramine (15 mg/kg, three times in a 21 h perio
d) significantly increased struggling and reduced immobility in Spragu
e-Dawley and Brown Norway rats, Wistar-Kyoto rats failed to respond to
the drug. After chronic treatment with imipramine (13 days plus the a
cute imipramine treatment at the end of the treatment period), the thr
ee strains showed a positive response that was always significantly gr
eater than the response to acute administration, but which was much lo
wer in Wistar-Kyoto than in the other two strains. Down-regulation of
both beta-adrenoceptors and 5-HT2 receptors was observed 24 h after th
e forced swimming test in acutely and chronically imipramine-treated r
ats of the three strains, except that in Sprague-Dawley rats beta-adre
noceptors did not change after acute imipramine. No significant decrea
se in 5-HT1 binding sites was observed in any strain. Acute imipramine
administration caused a similar anorexia in Wistar-Kyoto as in the ot
her strains and at least the same level of down-regulation of beta-adr
enoceptors and 5-HT2 receptor. Tn addition, serum imipramine levels on
the day after the last drug administration were higher in Wistar-Kyot
o than in the other two strains. All these data suggest that the subse
nsitivity 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 m
ight be therefore not only a good animal model of depressive-like (pas
sive) behavior, but also a model of resistance to antidepressants whic
h could be used to investigate the neurobiological basis of such resis
tance, which is also observed in some depressed patients. (C) 1997 Els
evier Science B.V.