Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Neuropharmacology. 2013 Jan;64:479-88. doi: 10.1016/j.neuropharm.2012.08.004. Epub 2012 Aug 23.
Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ~6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [¹¹C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy α4β2* subtype-selective agonist varenicline and the high-efficacy α7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
可卡因的使用与认知功能障碍有关，这可能会对治疗结果产生负面影响。一种改善认知的药理学策略涉及烟碱型乙酰胆碱受体（nAChR）的刺激。然而，慢性可卡因暴露对 nAChR 分布和功能的影响尚未得到描述。因此，本研究的一个目标是检查具有广泛可卡因自我给药史的恒河猴（n = 4；~6 年，平均摄入量为 1463mg/kg）与年龄匹配的可卡因未使用对照猴子（n = 5）之间 nAChR 的可用性。使用[¹¹C]-尼古丁和正电子发射断层扫描（PET）成像，可卡因经验丰富的猴子在海马体中的受体可用性明显高于可卡因未使用的猴子。第二个目标是检查这些相同猴子中 nAChR 激动剂对多种认知表现领域的影响。对于这些研究，使用延迟匹配样本（DMS）任务评估工作记忆，使用刺激辨别和反转学习任务评估联想学习和行为灵活性。当急性给予时，非选择性高效能激动剂尼古丁、低效能α4β2*亚型选择性激动剂伐尼克兰和高效能α7 亚型选择性激动剂 PNU-282987 均显著改善了可卡因未使用和可卡因经验丰富的猴子的 DMS 表现。在工作记忆上产生最大认知增强效果的尼古丁和伐尼克兰的个体剂量不会影响辨别或反转学习，而 PNU-282987 则破坏了可卡因未使用的猴子的反转学习。这些发现表明可卡因自我给药史影响了 nAChR 的分布以及 nAChR 激动剂对认知表现的影响，包括对反转学习的破坏作用的敏感性降低。nAChR 激动剂的认知增强作用可能与可卡因成瘾的行为治疗相结合而有益。本文是特刊“认知增强剂”的一部分。
