Chronic scopolamine-injection-induced cognitive deficit on reward-directed instrumental learning in rat is associated with CREB signaling activity in the cerebral cortex and dorsal hippocampus

Abstract

Scopolamine, a nonselective muscarinic receptor antagonist, has been used in experimental animal models of dementia. It has been demonstrated to disrupt performances in a battery of behavioral tests. However, no attempt has been made to determine how scopolamine-treated animals would respond to a series of reward-directed instrumental learning (RDIL) tasks. The present study was designed to investigate the effects of chronic intraperitoneal injection of scopolamine in Wistar rats on RDIL, as well as on the expression of memory-related molecules in the dorsal hippocampus (DH) and cerebral cortex (CCx). The effects of the pretraining injection of scopolamine on the acquisition of instrumental response (experiment 1) were first investigated. Then, the effects of post-training manipulation on the maintenance of instrumental response and the responses to changes in contingency degradation and signal discrimination were assessed (experiment 2). Finally, the expression of cyclic AMP response element-binding protein (CREB), phosphorylated CREB, and brain-derived neurotrophic factor in the DH and CCx were examined using Western blotting and enzyme-linked immunosorbent assay. The acquisition of instrumental conditioning is more vulnerable than its maintenance. The 3.0-mg/kg dose of scopolamine rendered rats unable to make adaptive changes in facing contingency degradation and correct responses in signal discrimination tasks. Furthermore, CREB signaling was inactivated by pretraining scopolamine treatment in both the DH and CCx. Nevertheless, this pathway was selectively suppressed by post-training treatment only in the CCx during memory reconsolidation. The results suggest that scopolamine-induced cognitive deficits on RDIL are related to the distinguishing alteration of CREB signaling in the DH and CCx.