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The Journal of Neuroscience, February 15, 2000, 20(4):1568-1574

Chronic Stress Induces Impairment of Spatial Working Memory Because of Prefrontal Dopaminergic Dysfunction

Kazushige Mizoguchi¹, Mitsutoshi Yuzurihara¹, Atsushi Ishige¹, Hiroshi Sasaki¹, De-Hua Chui², and Takeshi Tabira²

¹ Pharmacology Department, Central Research Laboratories, Tsumura and Company, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan, and ² Department of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan

Although the mechanism responsible for cognitive deficits in stress-related neuropsychiatric disorders has been obscure, prefrontal cortical (PFC) dopaminergic dysfunction is thought to be involved. In animals, the mesoprefrontal dopaminergic system is particularly vulnerable to stress, and chronic stress induces working memory impairment. However, the relation between the working memory impairment and altered dopaminergic activity in chronically stressed rats is unclear. Furthermore, the change of dopaminergic activity in the PFC induced by stress is thought to express as a stress response, not as a disorder of organic function. We have previously reported that chronic stress administered by water immersion and restraint for 4 weeks induces a organic disorder such as hippocampal neuronal degeneration. We therefore examined whether chronically stressed (4 weeks) and recovered (10 d) rats show a working memory impairment caused by reduced dopamine (DA) transmission in the PFC, as suspected in the neuropsychiatric disorders. The stress impaired the spatial working memory evaluated by T-maze task and induced a marked reduction of DA transmission concomitant with an increase in DA D1 receptor density in the PFC. This memory impairment was sufficiently ameliorated by intra-PFC infusion of 10 ng SKF 81297, a D1 receptor-specific agonist. Pretreatment with intraperitoneal injection of 20 µg/kg SCH 23390, a D1 receptor antagonist, reversed the SKF 81297 response. These results indicate that chronic stress induces working memory impairment through a D1 receptor-mediated hypodopaminergic mechanism in the PFC. These findings provide important information for understanding of the mechanisms underlying PFC dysfunction in stress-related neuropsychiatric disorders.

Key words: chronic stress; working memory; prefrontal cortex; dopaminergic neuron; D1 receptor; cognitive deficit

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2041568-07$05.00/0

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