Rationale

Menthol is a widely used tobacco constituent that has shown to enhance nicotine’s reinforcing effects.

Objective

To determine whether injected menthol also alters nicotine’s stimulus effects, we used a drug discrimination task.

Methods

A total of 57 adult Sprague-Dawley rats (28M, 29F) received 20 positive and 20 negative days (intermixed) of discrimination training. On positive days, rats received a group-specific menthol and nicotine injection (VEH + 0.1 NIC, 1 M + 0.1 NIC, 5 M + 0.1 NIC, VEH + 0.4 NIC, 1 M + 0.4 NIC, 5 M + 0.4 NIC; mg/kg) before eight 15-s cue light presentations (conditioned stimulus (CS)), each followed by 4-s sucrose access. On negative days, all rats were injected with vehicle and saline before eight non-reinforced CS presentations. Next, rats underwent generalization testing with 30 dose combinations of menthol and nicotine. The change in drug-mediated anticipatory goal tracking during the CS was calculated as a difference score (CS minus pre-CS responding).

Results

All groups readily acquired drug discrimination. However, difference scores for the 5M + 0.1 NIC group were lower for females. Additionally, females had lower scores for 0.05, 0.1, and 0.4 mg/kg nicotine generalization tests. The lowest nicotine dose discriminable from saline was 0.05 mg/kg for females but 0.025 mg/kg for males. Co-administration with 5 or 10 mg/kg menthol weakened discrimination performance between 0.1 and 0.4 mg/kg and between 0.1 and 0.05 mg/kg nicotine for 0.1 mg/kg nicotine training groups.

Conclusions

Female rats that were trained with 0.1 mg/kg nicotine were more sensitive to menthol’s modulatory effects on nicotine’s stimulus effects. This highlights the importance of taking sex and training dose into account when evaluating the interoceptive stimulus effects of nicotine and menthol.

中文翻译：

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薄荷醇减弱了尼古丁对雌性而非雄性大鼠的内感受判别刺激作用。

基本原理

薄荷醇是一种广泛使用的烟草成分，已证明可以增强尼古丁的强化作用。

客观的

为了确定注射的薄荷醇是否也会改变尼古丁的刺激作用，我们使用了药物鉴别任务。

方法

总共 57 只成年 Sprague-Dawley 大鼠（28M，29F）接受了 20 天阳性和 20 天阴性（混合）的歧视训练。在积极的日子里，大鼠接受组特定的薄荷醇和尼古丁注射（VEH + 0.1 NIC、1 M + 0.1 NIC、5 M + 0.1 NIC、VEH + 0.4 NIC、1 M + 0.4 NIC、5 M + 0.4 NIC；mg /kg) 在八次 15 秒的提示灯演示（条件刺激 (CS)）之前，每个都跟随着 4 秒的蔗糖访问。在消极日，所有大鼠在八次非强化 CS 演示之前注射载体和生理盐水。接下来，大鼠接受了薄荷醇和尼古丁的 30 种剂量组合的泛化测试。在 CS 期间药物介导的预期目标跟踪的变化计算为差异分数（CS 减去前 CS 响应）。

结果

所有群体都容易获得毒品歧视。然而，女性的 5M + 0.1 NIC 组的差异得分较低。此外，女性在 0.05、0.1 和 0.4 mg/kg 尼古丁泛化测试中的得分较低。与生理盐水可区分的最低尼古丁剂量，雌性为 0.05 mg/kg，而雄性为 0.025 mg/kg。对于 0.1 mg/kg 尼古丁训练组，与 5 或 10 mg/kg 薄荷醇共同给药会减弱 0.1 和 0.4 mg/kg 之间以及 0.1 和 0.05 mg/kg 尼古丁之间的鉴别性能。

结论

用 0.1 mg/kg 尼古丁训练的雌性大鼠对薄荷醇对尼古丁刺激作用的调节作用更敏感。这突出了在评估尼古丁和薄荷醇的内感受刺激作用时考虑性别和训练剂量的重要性。