Kelley Brian M, Rowan James D
Department of Psychology, Bridgewater College, 402 East College Street, P.O. Box 25, Bridgewater, VA 22812, USA.
Int J Dev Neurosci. 2004 Aug-Oct;22(5-6):339-48. doi: 10.1016/j.ijdevneu.2004.04.002.
Cigarette smoking by adolescents is a strong predictor of future drug use, abuse, and dependence. While this "gateway drug effect" is assumed to be related to psychosocial factors, data from our laboratory suggests that adolescent nicotine use may permanently disrupt reward systems through changes in dopamine receptor function. Behavioral pharmacological methods known to be indirectly (motor activity) and directly (conditioned-place-preference) related to drug reinforcement were used to examine changes in cocaine sensitivity. Testing was performed on adult mice that were exposed to nicotine (0.3, 1.0, and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (postnatal days 25-57). Prior to testing, subjects had a 28 day drug-free, time-off period. After acclimation to the testing apparatus, the locomotor effects (30 min, 30 cm traveled) of cocaine (5, 10, and 20 mg/kg, IP) were measured daily; cocaine tests were preceded and followed by saline control tests. Following the acute dose-response curve, mice received saline followed by 5 days of 20.0 mg/kg cocaine. Thereafter, mice underwent condition-place-preference testing. A pre-test was performed to determine compartment preference (i.e., no injection, 20 min test). Cocaine (10 mg/kg, IP) was paired with the subjects non-preferred side and saline with the other. Conditioning sessions were conducted for 8 days with the order of drug/saline injections counter-balanced across subjects. A drug-free, post-test occurred on the day following the final conditioning session. A dose-dependent relationship between adolescent nicotine exposure and cocaine reward was noted in the adult mice across both test conditions. Subjects exposed to nicotine showed an increased response to cocaine's motor activating effects and a decreased response to cocaine's rewarding effects. A follow-up study was undertaken to evaluate dopamine D1, D2, and D3 receptor function in adult mice exposed to the highest dose of nicotine from the first study. While both interesting and revealing, the results of motor activity tests with dopamine agonist only approached significance. Further research will be required to more fully examine the mechanism of action for the observed changes in cocaine reward. In summary, this is the first study to demonstrate a dose-response relationship between adolescent nicotine exposure and changes in cocaine reward and sensitivity during adulthood.
青少年吸烟是未来药物使用、滥用和成瘾的有力预测指标。虽然这种“入门药物效应”被认为与心理社会因素有关，但我们实验室的数据表明，青少年使用尼古丁可能会通过多巴胺受体功能的变化永久性地扰乱奖赏系统。已知与药物强化间接（运动活动）和直接（条件性位置偏爱）相关的行为药理学方法被用于检测可卡因敏感性的变化。对青春期（出生后第25 - 57天）接触尼古丁（0.3、1.0和3.0 mg/kg，皮下注射，周一至周五，每日两次）或生理盐水的成年小鼠进行测试。在测试前，实验对象有28天的无药停药期。适应测试设备后，每天测量可卡因（5、10和20 mg/kg，腹腔注射）的运动效应（30分钟，移动30厘米）；可卡因测试前后均进行生理盐水对照测试。在急性剂量反应曲线测试后，小鼠先接受生理盐水注射，然后接受5天20.0 mg/kg的可卡因注射。此后，小鼠接受条件性位置偏爱测试。进行预测试以确定隔室偏爱（即不注射，测试20分钟）。可卡因（10 mg/kg，腹腔注射）与实验对象不偏爱的一侧配对，生理盐水与另一侧配对。进行8天的条件训练，药物/生理盐水注射顺序在实验对象间进行平衡。在最后一次条件训练后的第二天进行无药后测试。在两种测试条件下，成年小鼠中均发现青少年尼古丁暴露与可卡因奖赏之间存在剂量依赖关系。接触尼古丁的实验对象对可卡因的运动激活效应反应增强，对可卡因的奖赏效应反应减弱。进行了一项后续研究，以评估在第一项研究中接触最高剂量尼古丁的成年小鼠的多巴胺D1、D2和D3受体功能。虽然多巴胺激动剂的运动活动测试结果既有趣又有启发性，但仅接近显著性。需要进一步研究以更全面地研究观察到的可卡因奖赏变化的作用机制。总之，这是第一项证明青少年尼古丁暴露与成年期可卡因奖赏和敏感性变化之间存在剂量反应关系的研究。
