Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction

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 mg/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.