Lárraga Armando, Belluzzi James D, Leslie Frances M
Department of Pharmacology, University of California Irvine, CA, USA.
Department of Pharmacology, University of CaliforniaIrvine, CA, USA; Department of Anatomy and Neurobiology, University of CaliforniaIrvine, CA, USA.
Front Behav Neurosci. 2017 Feb 22;11:25. doi: 10.3389/fnbeh.2017.00025. eCollection 2017.
Use of alcohol and tobacco, the two most concurrently abused drugs, typically first occurs during adolescence. Yet, there have been no systematic analyses of ethanol (EtOH) and nicotine (Nic) interactions during adolescence. Recent animal studies report that -opioid (KOR) receptor activation mediates age differences in drug reinforcement. Our hypothesis is that concurrent self-administration of EtOH and Nic will be greater in adolescent rats because of age differences in KOR function. Furthermore, exposure to alcohol and nicotine during adolescence has been reported to increase EtOH intake in adulthood. We performed a longitudinal animal study and hypothesized adolescent rats allowed to self-administer nicotine would drink more alcohol as adults. Adolescent, postnatal day (P)32, and adult (P90) male and female Sprague-Dawley rats were allowed to self-administer EtOH, Nic, or a combination of both, EtOH+Nic, in an intravenous self-administration paradigm. The role of KOR was pharmacologically evaluated with the KOR antagonist, norbinaltorphamine (norBNI) and with the KOR agonist, U50,488H. Alcohol drinking was subsequently evaluated with male rats in a drinking in the dark (DID), 2-bottle choice test. Concurrent Nic increased EtOH intake in adolescent males, but not in adults or females. Pharmacological blockade of KOR with norBNI robustly increased EtOH+Nic self-administration in adult male rats, but had no effect with female rats. Lastly, in our longitudinal study with male rats, we found prior self-administration of Nic or EtOH+Nic during adolescence increased subsequent oral EtOH intake, whereas prior self-administration of EtOH alone in adults increased subsequent EtOH drinking. There are major age- and sex-differences in the reinforcing effects of EtOH+Nic. Adolescent males are sensitive to the reinforcing interactions of the two drugs, whereas this effect is inhibited by KOR activation in male adults. Nicotine self-administration in adolescent males also increased subsequent oral EtOH intake. These findings suggest that brain mechanisms underlying the reinforcing effects of EtOH and nicotine are both age- and sex-dependent, and that tobacco or e-cigarette use may increase the vulnerability of teenage boys to alcohol abuse.
酒精和烟草是两种最常同时被滥用的药物，其使用通常始于青春期。然而，目前尚无关于青春期乙醇（EtOH）和尼古丁（Nic）相互作用的系统分析。最近的动物研究报告称，κ-阿片受体（KOR）激活介导了药物强化中的年龄差异。我们的假设是，由于KOR功能的年龄差异，青春期大鼠同时自我给药EtOH和Nic的情况会更常见。此外，据报道，青春期接触酒精和尼古丁会增加成年后的EtOH摄入量。我们进行了一项纵向动物研究，并假设允许自我给药尼古丁的青春期大鼠成年后会饮用更多酒精。在静脉自我给药范式中，对出生后第32天（P32）的青春期大鼠以及成年（P90）雄性和雌性Sprague-Dawley大鼠进行实验，使其自我给药EtOH、Nic或两者的组合EtOH+Nic。使用KOR拮抗剂诺宾吗啡（norBNI）和KOR激动剂U50,488H对KOR的作用进行药理学评估。随后，在黑暗中饮酒（DID）的两瓶选择试验中对雄性大鼠的酒精饮用情况进行评估。同时给予Nic会增加青春期雄性大鼠的EtOH摄入量，但对成年大鼠或雌性大鼠没有影响。用norBNI对KOR进行药理学阻断可显著增加成年雄性大鼠的EtOH+Nic自我给药量，但对雌性大鼠没有影响。最后，在我们对雄性大鼠的纵向研究中，我们发现青春期之前自我给药Nic或EtOH+Nic会增加随后的口服EtOH摄入量，而成年大鼠之前单独自我给药EtOH会增加随后的EtOH饮酒量。EtOH+Nic的强化作用存在主要的年龄和性别差异。青春期雄性大鼠对这两种药物的强化相互作用敏感，而这种作用在成年雄性大鼠中会被KOR激活所抑制。青春期雄性大鼠自我给药尼古丁也会增加随后的口服EtOH摄入量。这些发现表明，EtOH和尼古丁强化作用的脑机制既依赖于年龄也依赖于性别，并且使用烟草或电子烟可能会增加青少年男孩酗酒的易感性。
