Struik Dicky, Fadda Paola, Zara Tamara, Zamberletti Erica, Rubino Tiziana, Parolaro Daniela, Fratta Walter, Fattore Liana
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands.
Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554Km 4,500, 09042 Monserrato, CA, Italy; Centre of Excellence "Neurobiology of Dependence", University of Cagliari, Cittadella Universitaria di Monserrato, SS 554 Km 4,500, 09042 Monserrato, CA, Italy.
Pharmacol Res. 2017 Jan;115:209-217. doi: 10.1016/j.phrs.2016.11.031. Epub 2016 Nov 24.
Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CB receptor agonist WIN55,212-2 (WIN) in rats. Lister Hooded male rats were treated intramuscularly with nandrolone (15mg/kg) or vehicle for 14 consecutive days, and then allowed to self-administer WIN (12.5μg/kg/infusion) intravenously. After reaching stable drug intake, self-administration behavior was extinguished to examine drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Other behavioral parameters presumed to influence drug-taking and drug-seeking behaviors were examined to gain more insight into the behavioral specificity of nandrolone treatment. Finally, animals were sacrificed for analysis of CB receptor density and function in selected brain areas. We found that nandrolone-treated rats self-administered up to 2 times more cannabinoid than vehicle-treated rats, but behaved similarly to control rats when tested for drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Enhanced cannabinoid intake by nandrolone-treated rats was not accompanied by changes in locomotor activity, sensorimotor gating, or memory function. However, our molecular data show that after chronic WIN self-administration nandrolone-treated rats display altered CB receptor density and function in selected brain areas. We hypothesize that increased cannabinoid self-administration in nandrolone-treated rats results from a nandrolone-induced decrease in reward function, which rats seem to compensate by voluntarily increasing their cannabinoid intake. Altogether, our findings corroborate the hypothesis that chronic exposure to anabolic-androgenic steroids induces dysfunction of the reward pathway in rats and might represent a potential risk factor for abuse of cannabis and other drugs in humans.
临床和临床前观察表明，合成代谢雄激素类固醇可诱发神经生物学变化，从而改变滥用药物的奖赏效应。在本研究中，我们调查了合成代谢类固醇诺龙对大鼠体内大麻素CB受体激动剂WIN55,212-2（WIN）奖赏特性的影响。将利斯特 hooded 雄性大鼠连续14天肌肉注射诺龙（15mg/kg）或赋形剂，然后让其静脉内自我给药WIN（12.5μg/kg/输注）。在达到稳定的药物摄入量后，停止自我给药行为，以检查药物和线索诱导的大麻素寻求行为的恢复情况。还检查了其他推测会影响药物摄取和药物寻求行为的行为参数，以更深入了解诺龙治疗的行为特异性。最后，处死动物以分析选定脑区的CB受体密度和功能。我们发现，诺龙处理的大鼠自我给药的大麻素比赋形剂处理的大鼠多两倍，但在测试药物和线索诱导的大麻素寻求行为恢复时，其行为与对照大鼠相似。诺龙处理的大鼠大麻素摄入量增加，但并未伴随运动活动、感觉运动门控或记忆功能的变化。然而，我们的分子数据表明，在长期自我给药WIN后，诺龙处理的大鼠在选定脑区的CB受体密度和功能发生了改变。我们假设，诺龙处理的大鼠大麻素自我给药增加是由于诺龙诱导奖赏功能降低所致，大鼠似乎通过自愿增加大麻素摄入量来进行补偿。总之，我们的研究结果证实了以下假设：长期接触合成代谢雄激素类固醇会导致大鼠奖赏通路功能障碍，这可能是人类滥用大麻和其他药物的潜在风险因素。
