Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Psychoneuroendocrinology. 2010 Aug;35(7):1063-73. doi: 10.1016/j.psyneuen.2010.01.007. Epub 2010 Feb 6.
Anabolic-androgenic steroid (AAS) abuse is widespread. Moreover, AAS are reinforcing, as shown by self-administration in rodents. However, the receptors that transduce the reinforcing effects of AAS are unclear. AAS may bind to classical nuclear androgen receptors (ARs) or membrane receptors. We used two approaches to examine the role of nuclear ARs in AAS self-administration. First, we tested androgen self-administration in rats with the testicular feminization mutation (Tfm), which interferes with androgen binding. If nuclear ARs are essential for AAS self-administration, Tfm males should not self-administer androgens. Tfm males and wild-type (WT) littermates self-administered the non-aromatizable androgen dihydrotestosterone (DHT) or vehicle intracerebroventricularly (ICV) at fixed-ratio (FR) schedules up to FR5. Both Tfm and WT rats acquired a preference for the active nose-poke during DHT self-administration (66.4+/-9.6 responses/4 h for Tfm and 79.2+/-11.5 for WT responses/4 h), and nose-pokes increased as the FR requirement increased. Preference scores were significantly lower in rats self-administering vehicle (42.3+/-5.3 responses/4 h for Tfm and 19.1+/-4.0 responses/4 h for WT). We also tested self-administration of DHT conjugated to bovine serum albumin (BSA) at C3 and C17, which is limited to actions at the cell surface. Hamsters were allowed to self-administer DHT, BSA and DHT-BSA conjugates for 15 days at FR1. The hamsters showed a significant preference for DHT (18.0+/-4.1 responses/4 h) or DHT-BSA conjugates (10.0+/-3.7 responses/4 h and 21.0+/-7.2 responses/4 h), but not for BSA (2.5+/-2.4 responses/4 h). Taken together, these data demonstrate that nuclear ARs are not required for androgen self-administration. Furthermore, androgen self-administration may be mediated by plasma membrane receptors.
合成代谢雄激素类固醇（AAS）滥用现象普遍存在。此外，AAS 具有强化作用，这可通过啮齿动物的自身给药来证明。然而，传递 AAS 强化作用的受体尚不清楚。AAS 可能与经典的核雄激素受体（AR）或膜受体结合。我们使用两种方法来研究核 AR 在 AAS 自身给药中的作用。首先，我们在睾丸女性化突变（Tfm）大鼠中测试雄激素自身给药，该突变干扰雄激素结合。如果核 AR 对 AAS 自身给药至关重要，那么 Tfm 雄性不应自身给予雄激素。Tfm 雄性和野生型（WT）同窝仔鼠以固定比率（FR）方案经脑室内（ICV）给予非芳香化雄激素二氢睾酮（DHT）或载体，直至 FR5。Tfm 和 WT 大鼠在 DHT 自身给药期间都对主动鼻触表现出偏好（Tfm 为 66.4+/-9.6 次/4 h，WT 为 79.2+/-11.5 次/4 h），并且随着 FR 需求的增加，鼻触次数也增加。给予载体的大鼠的偏好评分明显较低（Tfm 为 42.3+/-5.3 次/4 h，WT 为 19.1+/-4.0 次/4 h）。我们还测试了 DHT 与牛血清白蛋白（BSA）在 C3 和 C17 处的缀合物的自身给药，该缀合物仅限于在细胞表面起作用。允许仓鼠在 FR1 下自行给予 DHT、BSA 和 DHT-BSA 缀合物 15 天。仓鼠对 DHT（18.0+/-4.1 次/4 h）或 DHT-BSA 缀合物（10.0+/-3.7 次/4 h 和 21.0+/-7.2 次/4 h）表现出明显的偏好，但对 BSA（2.5+/-2.4 次/4 h）没有偏好。总的来说，这些数据表明核 AR 不是雄激素自身给药所必需的。此外，雄激素自身给药可能由质膜受体介导。
