Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.
Addict Biol. 2020 Nov;25(6):e12828. doi: 10.1111/adb.12828. Epub 2019 Sep 5.
A significant portion of prescription opioid users self-administer orally rather than intravenously. Animal models of opioid addiction have demonstrated that intravenous cues are sufficient to cause drug seeking. However, intravenous models may not characterize oral users, and the preference to self-administer orally appears to be partially influenced by the user's sex. Our objectives were to determine whether oral opioid-associated cues are sufficient for relapse and whether sex differences exist in relapse susceptibility. Mice orally self-administered escalating doses of oxycodone under postprandial (prefed) or non-postprandial (no prefeeding) conditions. Both sexes demonstrated cue-induced reinstatement following abstinence. In separate mice, we found that oral oxycodone cues were sufficient to reinstate extinguished oral oxycodone-seeking behavior following abstinence without prior postprandial or water self-administration training. During self-administration, we incidentally found that female mice earned significantly more mg/kg oxycodone than male mice. Follow-up studies indicated sex differences in psychomotor stimulation and plasma oxycodone/oxymorphone following oral oxycodone administration. In addition, gonadal studies were performed in which we found divergent responses where ovariectomy-enhanced and orchiectomy-suppressed oral self-administration. While the suppressive effects of orchiectomy were identified across doses and postprandial conditions, the enhancing effects of ovariectomy were selective to non-postprandial conditions. These studies establish that (a) oral drug cues are sufficient to cause reinstatement that is independent of prandial conditions and water-seeking behavior, (b) earned oral oxycodone is larger in female mice compared with male mice potentially through differences in psychomotor stimulation and drug metabolism, and (c) gonadectomy produces divergent effects on oral oxycodone self-administration between sexes.
相当一部分处方类阿片药物使用者自行口服而非静脉注射。阿片成瘾的动物模型表明，静脉内线索足以引起觅药行为。然而，静脉内模型可能无法描述口服使用者的情况，而口服给药的偏好似乎部分受到使用者性别的影响。我们的目的是确定口服阿片类药物相关线索是否足以引起复吸，以及复吸易感性是否存在性别差异。在餐后（预喂食）或非餐后（无预喂食）条件下，小鼠经口自行给予递增剂量的羟考酮。两种性别的小鼠在禁欲后均表现出线索诱导的复吸。在单独的小鼠中，我们发现口服羟考酮线索足以在禁欲后重新激活已消除的口服羟考酮觅药行为，而无需预先进行餐后或水自我给药训练。在自我给药期间，我们偶然发现雌性小鼠摄入的羟考酮毫克/千克数明显高于雄性小鼠。后续研究表明，口服羟考酮给药后，在精神运动刺激和血浆羟考酮/羟吗啡酮方面存在性别差异。此外，还进行了性腺研究，发现卵巢切除术增强和睾丸切除术抑制口服自我给药存在不同的反应。虽然睾丸切除术的抑制作用在不同剂量和餐后条件下都存在，但卵巢切除术的增强作用仅选择性地出现在非餐后条件下。这些研究确立了以下几点：（a）口服药物线索足以引起复吸，而无需依赖进食条件和水觅药行为；（b）雌性小鼠通过精神运动刺激和药物代谢的差异，摄入的口服羟考酮比雄性小鼠更多；（c）去势对雄性和雌性小鼠的口服羟考酮自我给药产生了不同的影响。
