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The Journal of Neuroscience, June 16, 2004, 24(24):5492-5499; doi:10.1523/JNEUROSCI.0086-04.2004

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Behavioral/Systems/Cognitive
Endogenous Glucocorticoids Are Essential for Maintaining Prefrontal Cortical Cognitive Function

Kazushige Mizoguchi,¹ Atsushi Ishige,¹ Shuichi Takeda,¹ Masaki Aburada,¹ and Takeshi Tabira²

¹Pharmacology Department, Central Research Laboratories, Tsumura and Company, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan, and ²National Institute for Longevity Sciences, Morioka, Obu, Aichi 474-8522, Japan

Glucocorticoid hormones are important in the maintenance of many brain functions. Although their receptors are distributed abundantly throughout the brain, including the prefrontal cortex (PFC), it is not clear how glucocorticoid functions, particularly with regard to cognitive processing in the PFC. There is evidence of PFC cognitive deficits such as working memory impairment in several stress-related neuropsychiatric disorders, including depression, schizophrenia, and Parkinson's disease. Disruption of the hypothalamo-pituitary-adrenal (HPA) system, which is characterized by attenuated glucocorticoid negative feedback, is also observed. In rats, chronic stress induces working memory impairment as a result of decreased dopaminergic transmission in the PFC. These chronically stressed rats also show HPA disruption; this is caused in part by a reduced glucocorticoid response in the PFC. These findings implicate reduced glucocorticoid actions in working memory impairment. In the present study, we examined the effects of the suppression of endogenous glucocorticoids by adrenalectomy (ADX) on working memory in rats and explored the involvement of PFC dopaminergic activities in memory. The ADX impaired working memory, decreased dopamine release, and upregulated D₁ receptors in the PFC. These dysfunctions were prevented by corticosterone replacement that reproduced normal physiological plasma levels, indicating that suppression of glucocorticoids causes these dysfunctions. Moreover, the ADX-induced working memory impairment was ameliorated by intra-PFC infusions of a D₁ receptor agonist, SKF 81297. Thus, suppression of glucocorticoids impaired working memory through a D₁ receptor-mediated hypodopaminergic mechanism in the PFC. This finding indicates that endogenous glucocorticoids are essential for maintaining PFC cognitive function and suggests that HPA disruption contributes to PFC cognitive deficits.

Key words: adrenalectomy; glucocorticoid; dopamine; D₁ receptor; working memory; prefrontal cortex

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Received Jan 9, 2004; revised April 20, 2004; accepted April 27, 2004.

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