de Jong Inge E M, Oitzl Melly S, de Kloet E Ronald
Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, Division of Medical Pharmacology, Gorlaeus Laboratories, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Behav Brain Res. 2007 Feb 27;177(2):329-39. doi: 10.1016/j.bbr.2006.11.015. Epub 2006 Dec 5.
The objective of the present study was to investigate the contribution of adrenal stress hormones to strain differences in cocaine sensitivity. For this purpose, we have studied sensitisation to the locomotor stimulant effect of cocaine and, in parallel, cocaine-induced corticosterone secretion in two inbred mouse strains: C57BL/6 and DBA/2. Adrenalectomy ('ADX': surgical removal of the adrenal glands) was performed in a subset of animals to investigate the contribution of the adrenals. ADX and SHAM operated mice were subjected to repeated injections of cocaine (15.0mg/kg) or saline for nine consecutive days, followed by a 5-day withdrawal interval and a saline challenge on day 14. All animals were challenged with 7.5mg/kg cocaine on day 15. We report that repeated cocaine exposure induced locomotor sensitisation in both strains, while endocrine sensitisation was only observed in the DBA/2 strain. By contrast, cocaine attenuated corticosterone responses in C57BL/6 mice throughout the sensitisation paradigm. We have therefore identified one strain, the DBA/2 strain, that displays parallel sensitisation of cocaine-induced locomotion and -corticosterone secretion. Most interestingly, ADX prevented locomotor sensitisation only in DBA/2 mice, suggesting that behavioural sensitisation depends on the integrity of adrenal function and on secretion of adrenal glucocorticoids in this strain. The present results demonstrate that adrenal stress hormones facilitate behavioural sensitisation to cocaine in a genotype-dependent manner and suggest that glucocorticoids contribute to strain differences in psychostimulant sensitivity.
本研究的目的是调查肾上腺应激激素对可卡因敏感性品系差异的作用。为此，我们研究了两种近交系小鼠（C57BL/6和DBA/2）对可卡因运动刺激作用的敏感性，同时研究了可卡因诱导的皮质酮分泌情况。对一部分动物进行了肾上腺切除术（“ADX”：手术切除肾上腺），以研究肾上腺的作用。对接受ADX手术和假手术的小鼠连续九天反复注射可卡因（15.0mg/kg）或生理盐水，随后有5天的撤药期，并在第14天进行生理盐水激发试验。在第15天，所有动物均接受7.5mg/kg可卡因的激发试验。我们报告，反复接触可卡因在两个品系中均诱导了运动敏感性，而内分泌敏感性仅在DBA/2品系中观察到。相比之下，在整个敏感性实验范式中，可卡因减弱了C57BL/6小鼠的皮质酮反应。因此，我们确定了一个品系，即DBA/2品系，其显示出可卡因诱导的运动和皮质酮分泌的平行敏感性。最有趣的是，ADX仅在DBA/2小鼠中阻止了运动敏感性，这表明行为敏感性取决于该品系肾上腺功能的完整性和肾上腺糖皮质激素的分泌。目前的结果表明，肾上腺应激激素以基因型依赖的方式促进对可卡因的行为敏感性，并表明糖皮质激素导致了精神兴奋剂敏感性的品系差异。
