Smythe J W, Murphy D, Timothy C, Gul G H, Costall B
Department of Pharmacology, University of Bradford, West Yorkshire, UK.
Pharmacol Biochem Behav. 1997 Apr;56(4):613-21. doi: 10.1016/s0091-3057(96)00415-7.
Central cholinergic blockade with scopolamine (SCOP) produces profound cognitive impairments in human and animal subjects. We hypothesized that cognitive deficits induced by cholinergic blockade originate partly from its ability to enhance reactivity to the environment, an effect that would be ameliorated by prior mineralocorticoid receptor (MR) blockade, because MR antagonists reduce reactivity to novelty. In the present study, we investigated whether or not systemic or intrahippocampal infusions of the MR antagonist spironolactone (SPIRO) would affect SCOP-induced cognitive impairments in a water maze task. Adult male Lister hooded rats (350-450 g) served as subjects. In Experiment 1, rats were administered SPIRO (0 or 100 mg/kg i.p.) followed 10 min later by SCOP (0, 0.5, or 2.0 mg/kg i.p.; n = 10/group). In Experiment 2, groups of rats implanted with hippocampal cannulae received central infusions of SPIRO (50 ng/microliter; 3 microliters in total) 10 min prior to SCOP injection (2.0 mg/kg i.p.; n = 6/group). Behavioural testing started 15 min after SCOP administration and consisted of a simple water maze task in which animals were required to locate a submerged platform using spatial cues. The testing regime consisted of two phases: a) acquisition, and b) retention, 24 h later. Peripheral, but not central, injections of SPIRO enhanced water maze performance during acquisition in SCOP-treated rats, as shown by shorter latencies and shorter distances travelled to locate the hidden platform. Both peripheral and central SPIRO administration reduced the long-term retention deficits in performance in the SCOP-treated animals. These data are in general agreement with a growing body of research suggesting that corticosteroid hormones interact with central cholinergic systems to affect both physiological and behavioural responses. MR blockade may reduce an animal's reactivity to the environment and enable it to selectively filter out extraneous stimuli that it would otherwise react to, thus impairing performance.
东莨菪碱（SCOP）引起的中枢胆碱能阻滞会在人类和动物受试者中产生严重的认知障碍。我们推测，胆碱能阻滞引起的认知缺陷部分源于其增强对环境反应性的能力，而这种效应会因预先使用盐皮质激素受体（MR）拮抗剂而得到改善，因为MR拮抗剂会降低对新事物的反应性。在本研究中，我们调查了全身或海马内注射MR拮抗剂螺内酯（SPIRO）是否会影响水迷宫任务中SCOP引起的认知障碍。成年雄性利斯特戴帽大鼠（350 - 450克）作为实验对象。在实验1中，大鼠腹腔注射SPIRO（0或100毫克/千克），10分钟后腹腔注射SCOP（0、0.5或2.0毫克/千克；每组n = 10）。在实验2中，植入海马套管的大鼠组在注射SCOP（2.0毫克/千克腹腔注射）前10分钟接受海马内注射SPIRO（50纳克/微升；共3微升；每组n = 6）。在SCOP给药15分钟后开始行为测试，测试包括一个简单的水迷宫任务，要求动物利用空间线索找到水下平台。测试方案包括两个阶段：a）获取阶段，以及b）24小时后的保持阶段。在接受SCOP治疗的大鼠获取阶段，外周而非中枢注射SPIRO可提高水迷宫表现，表现为找到隐藏平台的潜伏期更短、游动距离更短。外周和中枢注射SPIRO均可减少接受SCOP治疗动物的长期保持表现缺陷。这些数据总体上与越来越多的研究一致，表明皮质类固醇激素与中枢胆碱能系统相互作用，影响生理和行为反应。MR阻断可能会降低动物对环境的反应性，并使其能够选择性地过滤掉原本会做出反应的无关刺激，从而损害表现。
