Lahmame A, del Arco C, Pazos A, Yritia M, Armario A
Departament de Biologia Cellular i Fisiologia, Facultat de Ciències, Universitat Autònoma de Barcelona, Spain.
Eur J Pharmacol. 1997 Oct 22;337(2-3):115-23. doi: 10.1016/s0014-2999(97)01276-4.
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.
据报道，Wistar-Kyoto大鼠在强迫游泳试验中非常被动。此外，它们对急性给予地昔帕明或8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）均无反应。在本实验中，研究了它们对急性和慢性给予丙咪嗪的反应以及与β-肾上腺素能受体、5-HT1和5-HT2受体下调的可能关系。Sprague-Dawley大鼠和Brown-Norway大鼠被纳入研究，因为先前已证明这两个品系对急性给予地昔帕明和8-OH-DPAT有反应。急性给予丙咪嗪（15mg/kg，24小时内给药三次）可显著增加Sprague-Dawley大鼠和Brown Norway大鼠的挣扎次数并减少不动时间，而Wistar-Kyoto大鼠对该药物无反应。在用丙咪嗪进行慢性治疗（13天，治疗期结束时加急性丙咪嗪治疗）后，三个品系均表现出阳性反应，且该反应始终显著大于急性给药后的反应，但Wistar-Kyoto大鼠的反应远低于其他两个品系。在三个品系中，急性和慢性丙咪嗪治疗的大鼠在强迫游泳试验后24小时均观察到β-肾上腺素能受体和5-HT2受体下调，但Sprague-Dawley大鼠急性给予丙咪嗪后β-肾上腺素能受体未发生变化。在任何品系中均未观察到5-HT1结合位点有显著减少。急性给予丙咪嗪在Wistar-Kyoto大鼠中引起的厌食与其他品系相似，且β-肾上腺素能受体和5-HT2受体下调程度至少相同。此外，末次给药后一天Wistar-Kyoto大鼠的血清丙咪嗪水平高于其他两个品系。所有这些数据表明，Wistar-Kyoto大鼠中观察到的对丙咪嗪的敏感性降低：（i）不能主要由药代动力学差异解释，（ii）似乎与单胺能系统无关。因此，Wistar-Kyoto大鼠可能不仅是抑郁样（被动）行为的良好动物模型，也是对抗抑郁药耐药的模型，可用于研究这种耐药性的神经生物学基础，这种耐药性在一些抑郁症患者中也有观察到。
