Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 104790, Durham, NC 27710, USA.
Psychopharmacology (Berl). 2011 Jun;215(4):621-30. doi: 10.1007/s00213-010-2161-8. Epub 2011 Jan 28.
Neuronal nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and nicotinic analogs improve attention and nicotinic antagonists impair it. This study was conducted to investigate the role of α4β2 nicotinic receptors in sustained attention using a novel selective α4β2 nicotinic receptor ligand, sazetidine-A.
Female rats were trained to perform the signal detection task to a stable baseline of accuracy. The rats were injected with saline, sazetidine-A (0.01, 0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their combination; or, in another experiment, the rats were injected with the same doses of sazetidine-A, scopolamine (0.02 mg/kg), or their combination.
Percent hit and percent correct rejection showed that dizocilpine caused significant (p < 0.025) impairments in performance, which were significantly reversed by each of the sazetidine-A doses. Response omissions were significantly (p < 0.05) increased by dizocilpine, and this was also significantly reversed by each of the sazetidine-A doses. None of the sazetidine-A doses had significant effects on hit, correct rejection, or response omissions when given alone. Scopolamine also caused significant (p < 0.0005) impairments in percent hit and percent correct rejection and increased response omissions, which were significantly attenuated by all the sazetidine-A doses for percent hit and response omissions and by the highest dose of sazetidine-A for percent correct rejection. Both scopolamine and dizocilpine significantly (p < 0.0005) increased response latency, an effect which was significantly attenuated by sazetidine-A coadministration.
These studies imply an important role for α4β2 nicotinic receptors in improving sustained attention under conditions that disrupt it. Very low doses of sazetidine-A or drugs with a similar profile may provide therapeutic benefit for reversing attentional impairment in patients suffering from mental disorders and/or cognitive impairment.
已经证实神经元烟碱型受体系统在认知中发挥关键作用。尼古丁和烟碱类似物可改善注意力，而烟碱拮抗剂则会损害注意力。本研究旨在使用新型选择性α4β2烟碱型受体配体，S-扎替啶-A，研究α4β2 烟碱型受体在维持注意力中的作用。
雌性大鼠接受信号检测任务训练，以达到稳定的准确率基线。大鼠被注射生理盐水、S-扎替啶-A（0.01、0.03 和 0.1mg/kg）、地卓西平（0.05mg/kg）或两者的组合；或者，在另一个实验中，大鼠被注射相同剂量的 S-扎替啶-A、东莨菪碱（0.02mg/kg）或两者的组合。
击中率和正确拒绝率表明，地卓西平导致大鼠的表现出现显著（p<0.025）损害，而 S-扎替啶-A 的每个剂量均显著逆转了这种损害。地卓西平显著增加了反应遗漏（p<0.05），而 S-扎替啶-A 的每个剂量也显著逆转了这种情况。当单独给予 S-扎替啶-A 时，其对击中率、正确拒绝率或反应遗漏没有显著影响。东莨菪碱也导致了显著的（p<0.0005）击中率和正确拒绝率下降和反应遗漏增加，而 S-扎替啶-A 的所有剂量均显著降低了击中率和反应遗漏，最高剂量的 S-扎替啶-A 也显著降低了正确拒绝率。东莨菪碱和地卓西平均显著（p<0.0005）增加了反应潜伏期，而 S-扎替啶-A 的共同给药显著减弱了这种影响。
这些研究表明，α4β2 烟碱型受体在改善破坏注意力的情况下的持续注意力方面发挥着重要作用。非常低剂量的 S-扎替啶-A 或具有类似特征的药物可能为治疗精神障碍和/或认知障碍患者的注意力损害提供治疗益处。
