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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

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Abstract

Rationale

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.

Objectives

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).

Methods

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.

Results

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.

Conclusions

The results suggest that scopolamine-induced cognitive deficits on RDIL are related to the distinguishing alteration of CREB signaling in the DH and CCx.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

CCx:

Cerebral cortex

CNS:

Central nervous system

CREB:

Cyclic AMP response element-binding protein

DH:

Dorsal hippocampus

FR:

Fixed ratio

p-CREB:

Phosphorylated CREB

RDIL:

Reward-directed instrumental learning

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (30973888) and the Ministry of Science and Technology of China (2011DFA32730 and 2012-ZX09J12201).

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Authors and Affiliations

  1. Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Malianwa North Road No. 151, Beijing, 100193, China

    Zhe Shi, Sidi Li & Xinmin Liu

  2. Hunan University of Traditional Chinese Medicine, Hanpu, Changsha, 410208, Hunan, China

    Lingling Chen, Jianguo Zeng & Yiran He

  3. China Astronaut Research and Training Center, Yuanmingyuan West Road No. 1, Beijing, 100094, China

    Shanguang Chen & Yinghui Li

  4. Comparative Medical Center, Peking Union Medical College and Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Panjiayuan Nanli No. 5, Beijing, 100021, China

    Xiuping Sun

  5. Medical Experimental Centre, Chinese Academy of Chinese Medical Sciences, Dongzhimen Nanxiaojie No. 16, Beijing, 100700, China

    Lihua Sun

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  1. Zhe Shi
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Correspondence to Xinmin Liu.

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Z. Shi and L. Chen, joint co-authors.

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Shi, Z., Chen, L., Li, S. et al. 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. Psychopharmacology 230, 245–260 (2013). https://doi.org/10.1007/s00213-013-3149-y

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