INSERM U862, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux Cedex, France.
Addict Biol. 2010 Jan;15(1):81-7. doi: 10.1111/j.1369-1600.2009.00178.x.
Corticosterone, the main glucorticoid hormone in rodents, facilitates behavioral responses to cocaine. Corticosterone is proposed to modulate cocaine intravenous self-administration (SA) and cocaine-induced locomotion through distinct receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), respectively. However, this remains debatable. On one hand, modulation of both responses by the GR was tested in different experimental conditions, i.e. light versus dark nycthemeral phase and naïve versus cocaine-experienced animals. On the other hand, modulation of both responses by the MR was never tested directly but only inferred based on the ability of low plasma corticosterone levels (those for which corticosterone almost exclusively binds the MR) to compensate the effects of adrenalectomy. Our goal here was to test the involvement of the GR and the MR in cocaine-induced locomotor and reinforcing effects in the same experimental conditions. C57Bl/6J mice were trained for cocaine (1 mg/kg/infusion) intravenous SA over 40 SA sessions. The animals were then administered with mifepristone (30 mg/kg i.p.), a GR antagonist, or with spironolactone (20 mg/kg/i.p.), an MR antagonist, 2 hours before either cocaine intravenous SA or cocaine-induced locomotion. In a comparable nycthemeral period and in similarly cocaine-experienced animals, a blockade of the GR decreased cocaine-induced reinforcing effects but not cocaine-induced locomotion. A blockade of the MR decreased both cocaine-induced reinforcing (but to a much lesser extent than the GR blockade) and locomotor effects. Altogether, our results comforted the hypothesis that the GR modulates cocaine-related operant conditioning, while the MR would modulate cocaine-related unconditioned effects. The present data also reveal mifepristone as an interesting tool for manipulating the impact of corticosterone on cocaine-induced reinforcing effects in mice.
皮质酮是啮齿动物中主要的糖皮质激素，有助于可卡因的行为反应。皮质酮被认为通过不同的受体——糖皮质激素受体（GR）和盐皮质激素受体（MR）——分别调节可卡因静脉自我给药（SA）和可卡因诱导的运动。然而，这仍然存在争议。一方面，GR 对这两种反应的调节作用已经在不同的实验条件下进行了测试，即在白天和黑夜的不同时间以及在无经验和可卡因经验的动物中进行了测试。另一方面，MR 对这两种反应的调节作用从未直接测试过，只是根据低血浆皮质酮水平（皮质酮几乎仅与 MR 结合）能够补偿肾上腺切除术的影响来推断。我们的目标是在相同的实验条件下测试 GR 和 MR 对可卡因诱导的运动和强化作用的参与情况。C57Bl/6J 小鼠接受了 40 次可卡因（1mg/kg/ 次）静脉 SA 训练。然后，在进行可卡因静脉 SA 或可卡因诱导的运动之前 2 小时，给动物注射米非司酮（30mg/kg，ip），一种 GR 拮抗剂，或螺内酯（20mg/kg，ip），一种 MR 拮抗剂。在相似的昼夜节律期和相似的可卡因经验动物中，GR 阻断剂减少了可卡因的强化作用，但不减少可卡因诱导的运动作用。MR 阻断剂减少了可卡因的强化作用（但程度远低于 GR 阻断剂）和运动作用。总之，我们的结果证实了这样一种假设，即 GR 调节与可卡因相关的操作性条件反射，而 MR 则调节与可卡因相关的非条件反射效应。本研究数据还表明，米非司酮是一种用于操纵皮质酮对小鼠可卡因诱导的强化作用的有趣工具。
