Impairment of dopaminergic system function after chronic treatment with corticotropin-releasing factor

Mounting evidence suggests that chronic stress may have a detrimental effect on dopaminergic function and, in certain individuals, could contribute to the pathophysiology of central nervous system disorders like depression, schizophrenia, and Parkinson's disease. Therefore, the effects of chronic elevated brain levels of corticotropin-releasing factor (CRF), a crucial mediator of the behavioral stress response, on dopaminergic function were investigated. Rats treated intracerebroventricularly (i.c.v.) with 1 μg of CRF per day for 13 days displayed a decreased stereotyped response to d-amphetamine 1 day after chronic CRF and 1 month post-CRF. These rats also displayed an increased cataleptic response to eticlopride at 2 days post-CRF, consistent with decreased functional activity in the dopaminergic systems. CRF treatment induced a transient decrease of dopamine tissue levels in the prefrontal cortex at 1 day and 1 week post-CRF, an increase in the nucleus accumbens 1 week post-CRF and no change in the striatum. An increase of the dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio, an indicator of dopamine turnover, also was seen in the prefrontal cortex and striatum in CRF-treated animals at 1 week post-CRF. The dopaminergic system is very sensitive to oxidative insults. Levels of malondialdehyde, a membrane lipid peroxidation marker, also were measured in the same brain areas. In the prefrontal cortex, we observed a decrease of malondialdehyde at 1 week after chronic CRF treatment. This result may indicate an activation of the antioxidant system in response to chronic stress. These results show that chronic hyperactivity of the CRF system leads to a transient dysfunction of the dopaminergic systems, possibly through oxidative mechanisms, and suggest that stress could be a cofactor in the pathogenesis and/or progression of disorders of the dopaminergic systems.