Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.
Addict Biol. 2021 Mar;26(2):e12900. doi: 10.1111/adb.12900. Epub 2020 Mar 24.
N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm ). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.
N-乙酰半胱氨酸（NAC）是一种半胱氨酸前体药物，已在临床前研究中显示可减少可卡因和线索引发的可卡因觅药行为的复燃。在这项住院研究中，研究人员检查了 NAC 维持治疗与安慰剂对非治疗寻求、可卡因依赖个体在可卡因引发和非引发自我给药期间可卡因觅药行为的影响。12 名参与者完成了这项双盲、安慰剂对照、自身交叉研究。每位参与者接受为期一周（周六至周五）的 NAC（TID 1200mg；每天总计 3600mg）维持治疗和一周的安慰剂（TID 0mg）治疗；药物顺序随机化。一部分参与者（n = 8）在药物治疗的第三天（周一）接受质子磁共振波谱扫描，以评估额前扣带皮层（rACC；体素 = 4.5cm）的神经化学。在每周的四个随机治疗日（周二至周五）中，每位参与者在吸入活性或安慰剂可卡因引发剂量（110mg 对 4mg）后，可以通过选择，递增比例方案获得单位量的可卡因（10mg，固定）与金钱（50 美分对 1.50 美元）。与安慰剂引发剂量相比，活性可卡因引发剂量（110mg）增加了可卡因觅药行为（p =.003）。与安慰剂水平相比，NAC 降低了可卡因引发的可卡因觅药行为（p =.044），但未改变安慰剂引发的可卡因觅药行为。较大的金钱替代物（1.50 美元）相对于较小的金钱替代物（0.50 美元）抑制了可卡因觅药行为（p =.011）。与安慰剂水平相比，NAC 显著降低了 rACC 谷氨酸+谷氨酰胺水平（p =.035），并在数值上降低了 rACC 谷氨酸水平（p =.085）。这些初步发现表明，NAC 抑制了某些但不是所有实验场景中的可卡因觅药行为。此外，我们的研究结果表明，NAC 通过调节 rACC 中的兴奋性来发挥其治疗作用。
