A negative feedback loop exists between the immune an central nervous systems, in which immune/pro-inflammatory mediators signal the hypothalamic-pituitary-adrenal axis to induce glucocorticoid-mediated restraint of the immune response. We have established the physiologic significance of this feedback loop in our studies in Lewis (LEW/N) rats, in which we have shown that susceptibility to inflammatory arthritis is related to a defect in the central component of this negative feedback loop, resulting in deficient CRH responses to challenge with a variety of inflammatory and stress mediators. We now extend these initial studies to show that the lEW/N CRH stress hyporesponsiveness, relateive to other strains, is profound, and extends across a variety of neurotransmitters and behavioral stressors. It appears as early in ontogeny as postnatal Day 14, and indicates that LEW/N rats fail to emerge from the stress-hyporesponsive period. It is associated with a variety of defined behavioral patterns, consistent with the differential HPA axis and neurotransmitter responsiveness of these two strains. Although several neurotransmitter systems do not differ in these strains (norepinephrine, 5HT2, acetylcholine), the benzodiazepine/GABA receptor complex, 5-HT1A system, and glucocorticoid Type 1 and Type 2 receptor systems differ in receptor number and/or ligand metabolism in these strains. The differences are organ and/or CNS site specific, and may be secondary to or play a causal role in the CRH hyporesponsiveness, and could contribute to or amplify some of the behavioral and/or inflammatory disease phenotypes in these strains. Thus, the lEW/N rat represents an example of a genetically based HPA axis hyporesponsiveness associated with susceptibility to inflammatory and behavioral disease.
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