Cognitive Dysfunctions Induced by Scopolamine Are Reduced by Systemic or Intrahippocampal Mineralocorticoid Receptor Blockade

Abstract

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 IP) followed 10 min later by SCOP (0, 0.5, or 2.0 mg/kg IP; n = 10/group). In Experiment 2, groups of rats implanted with hippocampal cannulae received central infusions of SPIRO (50 ng/μl; 3 μl in total) 10 min prior to SCOP injection (2.0 mg/kg IP; 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.