Muir J L, Everitt B J, Robbins T W
Department of Experimental Psychology, University of Cambridge, UK.
Psychopharmacology (Berl). 1995 Mar;118(1):82-92. doi: 10.1007/BF02245253.
To investigate further the cholinergic specificity of the effects of basal forebrain lesion-induced disruption of attentional performance, the present study examined the efficacy of various pharmacological agents in improving performance of a five-choice serial reaction time task in rats that had received lesions of the cholinergic basal forebrain. Specifically, the effects of the novel 5-HT3 receptor antagonist, ondansetron (0.3, 1, 10 ng/kg), and of nicotine (0.03, 0.06, 0.1, 0.3 mg/kg) and the anticholinesterase, physostigmine (0.05, 0.1 mg/kg), on attentional function were examined in animals which had received AMPA-induced lesions of the nucleus basalis magnocellularis (nbM). The behavioural impairments observed immediately following the lesion were a reduction were choice accuracy and an increase in correct response latency. Although these impairments showed recovery over the course of the following weeks, the deficit in choice accuracy could be reinstated by reducing the duration of the visual stimulus and thus increasing the attentional load placed on the animals. This reduction in choice accuracy could be dose dependently improved by systemic administration of either physostigmine or nicotine, suggesting that this impairment in attentional function may be attributed to disruption of cholinergic function. The pharmacological specificity of these improvements was supported by the inability of d-amphetamine to improve task performance (0.2, 0.4, 0.8 mg/kg). Ondansetron was also unable to improve accuracy of performance in lesioned animals, but was effective in reducing the anticipatory or premature responding observed in both control and lesioned animals, even when elevated (in the case of controls) by treatment with systemic d-amphetamine. The results of the present study therefore suggest that cholinergic dysfunction can lead to attentional impairments which can be ameliorated by cholinergic treatments such as physostigmine and nicotine, but that ondansetron, despite its proposed ability to release cortical acetylcholine, was unable to restore choice accuracy at the doses employed. The results further suggest a double dissociation of effects on accuracy and the disinhibition of responding.
为了进一步研究基底前脑损伤引起的注意力表现破坏效应的胆碱能特异性，本研究考察了各种药理剂对接受胆碱能基底前脑损伤的大鼠在五项选择连续反应时任务中的表现改善效果。具体而言，研究了新型5-羟色胺3（5-HT3）受体拮抗剂昂丹司琼（0.3、1、10纳克/千克）、尼古丁（0.03、0.06、0.1、0.3毫克/千克）以及抗胆碱酯酶药毒扁豆碱（0.05、0.1毫克/千克）对接受α-氨基-3-羟基-5-甲基-4-异唑丙酸（AMPA）诱导的大细胞基底核（nbM）损伤的动物注意力功能（的影响）。损伤后立即观察到的行为损伤包括选择准确性降低和正确反应潜伏期增加。尽管这些损伤在接下来的几周内有所恢复，但通过缩短视觉刺激持续时间从而增加施加于动物的注意力负荷，选择准确性的缺陷可以再次出现。通过全身给予毒扁豆碱或尼古丁，这种选择准确性的降低可以呈剂量依赖性地得到改善，这表明这种注意力功能损伤可能归因于胆碱能功能的破坏。这些改善的药理特异性得到了右旋苯丙胺（0.2、0.4、0.8毫克/千克）无法改善任务表现的支持。昂丹司琼也无法改善损伤动物的表现准确性，但能有效减少在对照动物和损伤动物中均观察到的预期性或过早反应，即使在对照动物中这种反应因全身给予右旋苯丙胺而增强时也是如此。因此，本研究结果表明，胆碱能功能障碍可导致注意力损伤，而这种损伤可通过毒扁豆碱和尼古丁之类的胆碱能治疗得到改善，但昂丹司琼尽管具有所提出的释放皮质乙酰胆碱的能力，在所使用的剂量下却无法恢复选择准确性。结果还进一步表明了对准确性的影响和反应去抑制之间的双重分离。
