Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Psychopharmacology (Berl). 2011 Jul;216(2):267-77. doi: 10.1007/s00213-011-2213-8. Epub 2011 Feb 18.
Treatment of the most widely abused drugs, nicotine and alcohol, is hampered by high rates of relapse. Varenicline tartrate, an α4β2 nicotinic receptor partial agonist, is currently prescribed as a smoking cessation aid. However, there is emerging evidence that it may also modulate alcohol seeking and cognitive functioning in rats.
As preclinical data on alcohol taking and relapse are limited, we used a self-administration-reinstatement model to evaluate the effects of varenicline on operant responding for alcohol (12%, v/v), intravenous nicotine (40 μg/kg/inf.), sucrose (10%, w/v) and on cue-induced relapse to alcohol and nicotine seeking in rats. At the cognitive level, we assed varenicline's effects on 5-choice serial reaction time task (5-CSRTT) performance with a focus on correct responses (attention) and premature responding (impulsivity), modalities that have previously been associated with addictive behaviour.
Varenicline, at doses of 1.5 and 2.5 mg/kg, reduced alcohol and nicotine self-administration and enhanced operant responding for sucrose. At these doses, varenicline reduced cue-induced relapse to alcohol, but not nicotine seeking. In contrast, at 0.5 mg/kg, varenicline facilitated cue-induced nicotine seeking. Similar to nicotine, varenicline increased premature responding at low doses, but had no effect on any of the other behavioural parameters in the 5-CSRTT.
Our data indicate that varenicline specifically reduced responding for nicotine and alcohol, but not for natural reinforcers such as sucrose. Interestingly, varenicline strongly attenuated cue-induced relapse to alcohol seeking, but not nicotine seeking. Varenicline may therefore be a promising aid in the treatment of alcohol addiction.
尼古丁和酒精是滥用最广泛的两种药物，但其治疗效果却因高复发率而受阻。酒石酸伐仑克林是一种α4β2 型烟碱受体部分激动剂，目前被开处方用作戒烟辅助药物。然而，越来越多的证据表明，它可能也能调节大鼠的酒精觅药行为和认知功能。
由于关于酒精摄入和复发的临床前数据有限，我们使用了一种操作性条件反射-复吸模型，来评估伐仑克林对大鼠酒精（12%，v/v）、静脉内尼古丁（40μg/kg/ 注射）、蔗糖（10%，w/v）的操作性反应以及对酒精和尼古丁觅药的线索诱导复吸的影响。在认知水平上，我们评估了伐仑克林对 5 选择连续反应时任务（5-CSRTT）表现的影响，重点关注正确反应（注意力）和过早反应（冲动性），这两种模态先前与成瘾行为有关。
伐仑克林的剂量为 1.5 和 2.5mg/kg 时，可减少酒精和尼古丁的自我给药，并增强蔗糖的操作性反应。在这些剂量下，伐仑克林可减少对酒精的线索诱导复吸，但不能减少对尼古丁的线索诱导复吸。相比之下，在 0.5mg/kg 时，伐仑克林促进了对尼古丁的线索诱导觅药。与尼古丁类似，伐仑克林在低剂量时增加了过早反应，但对 5-CSRTT 中的其他行为参数没有影响。
我们的数据表明，伐仑克林特异性地减少了对尼古丁和酒精的反应，但对自然强化物（如蔗糖）没有影响。有趣的是，伐仑克林强烈抑制了对酒精觅药的线索诱导复吸，但对尼古丁觅药的线索诱导复吸没有影响。因此，伐仑克林可能是治疗酒精成瘾的一种很有前途的辅助药物。
