Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA.
Department of Psychology, Jacksonville State University, Jacksonville, Alabama, USA.
Addict Biol. 2022 Mar;27(2):e13151. doi: 10.1111/adb.13151.
Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but >50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.
尼古丁成瘾是一种慢性复发性脑部疾病，吸烟是美国可预防死亡的主要原因。目前，戒烟最有效的药物治疗是伐伦克林（VRN），它可以减少尼古丁的正性和负性强化作用。临床上，VRN 可以减轻戒断症状并促进戒烟，但>50%的吸烟者在戒烟尝试后 3 个月内复发。这可能表明 VRN 未能改善促进复发易感性的尼古丁诱导的神经可塑性成分。动物模型表明，伏隔核中的谷氨酸失调与尼古丁复发有关。N-乙酰半胱氨酸（NAC）可使谷氨酸传递正常化并延长可卡因戒断。因此，将 VRN 和 NAC 联合使用可能分别促进和维持尼古丁戒断。在大鼠中，我们发现 VRN 有效减少了早期戒断期间的尼古丁自我给药和觅药行为，但对后期戒断期间的觅药行为没有影响。相比之下，NAC 仅减少后期戒断期间的觅药行为。由于 VRN 和 NAC 有时会引起轻微的不良反应，我们还评估了一种联合用药的序贯方法，即在自我给药和早期戒断期间使用亚治疗剂量的 VRN，在后期戒断期间使用亚治疗剂量的 NAC。正如预期的那样，亚治疗剂量的 VRN 没有减少尼古丁的摄入。然而，亚治疗剂量的 VRN 和 NAC 减少了后期戒断期间的觅药行为，表明存在联合效应。总的来说，我们的研究结果表明，联合使用亚治疗剂量的 VRN 和 NAC 是一种可行的、针对药物的方法，可以促进戒烟和减少复发，同时最大限度地减少不良反应。我们的数据还表明，成瘾的不同成分和时间点会激活 VRN 和 NAC 针对的不同神经回路。
