Grottick A J, Higgins G A
Preclinical CNS Research, Pharma Division, F. Hoffmann-La Roche Ltd., 4070, Basel, Switzerland.
Behav Brain Res. 2000 Dec 20;117(1-2):197-208. doi: 10.1016/s0166-4328(00)00305-3.
Nicotine can improve attentional functioning in humans, and a number of studies have recently demonstrated that under specific task conditions, nicotine can also improve attention in the rat. Neuronal nicotinic receptors comprise combinations of alpha(2-9) and beta(2-4) subunits, arranged to form a pentameric receptor, with the principal CNS subtypes currently believed to be alpha(4)beta(2) and a homomeric alpha(7) receptor. In the present studies, we attempted to delineate the particular nicotinic receptor subtype(s) contributing to the effects of nicotine on attention by assessing various nicotinic ligands on performance in the five-choice serial reaction time task (5-CSRTT). In rats performing below criterion (<80% correct, >20% omissions to a 1-s visual stimulus), subchronic dosing with nicotine (0.2 mg/kg sc) and the alpha(4)beta(2) agonist SIB 1765F (5 mg/kg sc) increased correct responding and decreased response latencies across the treatment week; whereas the alpha(7) agonist AR-R 17779 (20 mg/kg sc) was without effect. In subjects meeting the criterion, the competitive high affinity (including alpha(4)beta(2)) nicotine receptor antagonist DHbetaE (1-10 mg/kg sc) and the alpha(7) antagonist methyllycaconitine (MLA: 5-10 mg/kg i.p.) did not disrupt performance, whereas at the highest dose, the non-competitive antagonist mecamylamine (0.3-3 mg/kg sc) decreased accuracy and increased response latencies. These changes bore some similarities to those of pre-feeding and the non-competitive NMDA antagonist dizocilpine (0.03-0.06 mg/kg sc), suggesting that mecamylamine-induced performance disruption may relate to non-nicotinic receptor effects. In subjects chronically treated with nicotine, acute nicotine challenge (0.4 mg/kg sc) significantly increased accuracy whilst having no effect on any other performance measures. Finally, in these same nicotine pre-treated rats, the decrease in latency and increase in premature responses induced by nicotine (0.2 mg/kg sc) to a target stimulus of 150 ms was fully antagonised by DHbetaE (3 mg/kg sc) but not MLA (5 mg/kg i.p.). These results suggest that alpha(7) receptors do not play a role in any of the behavioural effects of nicotine observed in the 5-CSRTT, whereas a high affinity site, perhaps alpha(4)beta(2), is more likely involved.
尼古丁可改善人类的注意力功能，最近有多项研究表明，在特定任务条件下，尼古丁也能提高大鼠的注意力。神经元烟碱型受体由α（2 - 9）和β（2 - 4）亚基组合而成，排列形成五聚体受体，目前认为主要的中枢神经系统亚型是α（4）β（2）和同聚体α（7）受体。在本研究中，我们试图通过评估各种烟碱配体对五选择连续反应时任务（5 - CSRTT）表现的影响，来确定对尼古丁注意力效应有贡献的特定烟碱受体亚型。在表现低于标准（对1秒视觉刺激的正确反应<80%，遗漏反应>20%）的大鼠中，亚慢性给予尼古丁（0.2 mg/kg皮下注射）和α（4）β（2）激动剂SIB 1765F（5 mg/kg皮下注射），在整个治疗周内增加了正确反应并缩短了反应潜伏期；而α（7）激动剂AR - R 17779（20 mg/kg皮下注射）则没有效果。在达到标准的受试者中，竞争性高亲和力（包括α（4）β（2））烟碱受体拮抗剂DHβE（1 - 10 mg/kg皮下注射）和α（7）拮抗剂甲基lycaconitine（MLA：5 - 10 mg/kg腹腔注射）并未干扰表现，而在最高剂量时，非竞争性拮抗剂美加明（0.3 - 3 mg/kg皮下注射）降低了准确性并增加了反应潜伏期。这些变化与预喂食和非竞争性NMDA拮抗剂地佐环平（0.03 - 0.06 mg/kg皮下注射）引起的变化有一些相似之处，表明美加明引起的表现干扰可能与非烟碱受体效应有关。在长期接受尼古丁治疗的受试者中，急性尼古丁激发（0.4 mg/kg皮下注射）显著提高了准确性，而对任何其他表现指标均无影响。最后，在这些同样经过尼古丁预处理的大鼠中，尼古丁（0.2 mg/kg皮下注射）对150毫秒目标刺激引起的潜伏期缩短和过早反应增加，被DHβE（3 mg/kg皮下注射）完全拮抗，但未被MLA（5 mg/kg腹腔注射）拮抗。这些结果表明，α（7）受体在5 - CSRTT中观察到的尼古丁任何行为效应中均不起作用，而一个高亲和力位点，可能是α（4）β（2），更有可能参与其中。
