Lurcher mutant mice which are mainly known for their cerebellar degeneration, also display a hyperinducibility of proinflammatory cytokines, such as interleukin-1alpha and beta (IL-1) and tumor necrosis factor alpha (TNF-alpha), in peripheral macrophages. To assess whether this increased responsiveness to inflammatory stimuli is accompanied by a higher pituitary-adrenal response, we compared the adrenocorticotropic hormone (ACTH) and corticosterone response of Lc and wild-type mice to intraperitoneal (i.p.) administration of a cytokine inducer, lipopolysaccharide (LPS). Lurcher mice display resting levels of ACTH and corticosterone similar to those of wild-type mice. LPS (1.25 microg/g) induces a corticosterone surge 2-fold higher in Lurcher than in wild-type mice. By contrast, the response to IL-1alpha (10 ng/g, i.p.) is similar in both genotypes, suggesting that a differential reactivity of the hypothalamo-pituitary adrenal axis to IL-1 does not account for the higher reactivity of Lurcher mice to LPS. To test whether the increased responsiveness of the pituitary-adrenal axis of Lurcher mice generalizes accross stressors, mice were exposed to a novel environment. This condition also induced a surge of ACTH and corticosterone 3.5- and 2-fold higher in Lurcher than in wild-type mice. Prior blockade of IL-1 receptors by injection of IL-1 receptor antagonist (10 microg/g, i.p.) failed to block the response to LPS injection and exposure to novelty. In contrast, immunoneutralization of hypothalamic corticotropin-releasing hormone (CRH) significantly attenuated the ACTH surge and abrogated the difference between Lurcher and wild-type mice in their responses to a novel environment, suggesting that hypothalamic CRH neurons are involved in this excessive response.