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β-Carbolines found in cigarette smoke elevate intracranial self-stimulation thresholds in rats.
Pharmacology Biochemistry and Behavior ( IF 3.6 ) Pub Date : 2020-09-11 , DOI: 10.1016/j.pbb.2020.173041
Andrew C Harris 1 , Peter Muelken 2 , Mark G LeSage 1
Affiliation  

Identifying novel constituents that contribute to tobacco addiction is essential for developing more effective treatments and informing FDA regulation of tobacco products. While preclinical data indicate that monoamine oxidase (MAO) inhibitors can have abuse liability or potentiate the addiction-related effects of nicotine, most of these studies have used clinical MAO inhibitors (e.g., tranylcypromine) that are not present in cigarette smoke. The primary goal of this study was to evaluate the abuse potential of the β-carbolines harmane, norharmane, and harmine - MAO inhibitors that are found in cigarette smoke - in an intracranial self-simulation (ICSS) model in rats. A secondary goal was to evaluate the ability of norharmane to influence nicotine's acute effects on ICSS. None of the β-carbolines lowered ICSS thresholds at any dose studied when administered alone, suggesting a lack of abuse liability. Rather, all three β-carbolines produced dose-dependent elevations in ICSS thresholds, indicating aversive/anhedonic effects. Harmane and harmine also elevated ICSS response latencies, suggesting a disruption of motor function, albeit with reduced potency compared to their ICSS threshold-elevating effects. Norharmane (2.5 mg/kg) modestly attenuated the effects of nicotine on ICSS thresholds. Our findings indicate that these β-carbolines produced only aversive/anhedonic effects in an ICSS model when administered alone, and that norharmane unexpectedly attenuated nicotines acute effects on ICSS. Future work evaluating the addiction-related effects of nicotine combined with these and other MAO inhibitors present in smoke may be useful for understanding the role of MAO inhibition in tobacco addiction and informing FDA tobacco regulation.



中文翻译:

在香烟烟雾中发现的 β-咔啉可提高大鼠的颅内自我刺激阈值。

确定导致烟草成瘾的新成分对于开发更有效的治疗方法和告知 FDA 对烟草产品的监管至关重要。虽然临床前数据表明单胺氧化酶 (MAO) 抑制剂可能具有滥用倾向或增强尼古丁的成瘾相关作用,但大多数这些研究使用了香烟烟雾中不存在的临床 MAO 抑制剂(例如反苯环丙胺)。本研究的主要目标是在大鼠颅内自模拟 (ICSS) 模型中评估 β-咔啉甘胺、去甲甘烷和甘胺(香烟烟雾中发现的 MAO 抑制剂)的滥用潜力。次要目标是评估norharmane 影响尼古丁对ICSS 的急性影响的能力。单独给药时,任何研究剂量的 β-咔啉均未降低 ICSS 阈值,表明不存在滥用倾向。相反,所有三种 β-咔啉都产生了 ICSS 阈值的剂量依赖性升高,表明厌恶/快感效应。Harmane 和harmine 还提高了ICSS 反应延迟,表明运动功能受到干扰,尽管与其提高ICSS 阈值的作用相比效力降低。Norharmane (2.5 mg/kg) 适度减弱尼古丁对 ICSS 阈值的影响。我们的研究结果表明,当单独给药时,这些 β-咔啉仅在 ICSS 模型中产生厌恶/快感效应,并且去甲肾上腺素出人意料地减弱了尼古丁对 ICSS 的急性影响。

更新日期:2020-09-18
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