Neurotransmitter-lnduced hypothalamic-pituitary-adrenal axis responsiveness is defective in inflammatory disease-susceptible lewis rats: In vivo and in vitro studies suggesting globally defective hypothalamic secretion of corticotropin-releasing hormone

Aldo E. Calogero, Esther M. Sternberg, Gyorgy Bagdy, Craig Smith, Renato Bernardini, Sofia Aksentijevich, Ronald L. Wilder, Philip W. Gold, George P. Chrousos

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The susceptibility of female Lewis (LEW/N) rats to Ihe development of streptococcal cell wall (SCW)-induced arthritis and other autoimmune phenomena is associated with the inability of their hyp o thai am i c-pi tuitaty-adrenal (HPA) axis to adequately respond to inflammatory stimuli. In contrast, resistance to the development of SCW-induced arthritis and other inflammatory autoimmune manifestations in histocompatible female Fischer rats (F344/N) is related to their intact HPA axis response to inflammatory mediators. To evaluate the mechanism and the specificity of the HIPA axis defect in LEW/N rats, we examined the ability of three major excitatory neurotransmitter systems to activate the HPA axis in both Lewis and Fisher rats. The responsiveness of plasma ACTH and corticosterone to the cholinergic muscarinic receptor agonist areeoline, the α1-adrenergic receptor agonist methoxamine and the serotonin (5-HT)type 2 receptor agonist 1-(2, 5-dimethoxy-4-iodo-phenyl)2-aminopropane were significantly blunted and/or abolished in LEW/N compared to F344/N rats. To localize the HPA axis defect to the hypothalamic CRH neuron, we evaluated the ability ofexplanted hypothalami from the two strains to secrete immunoreac-tive CRH in vitro, in response to acetylcholine (ACh), norepinephrine (NE). 5-HT and the 5-HT agonist quipazine. LEW/N hypothalami released less immunoreactive CRH (iCRH) in response to ACh, NE, 5-HT and quipazine than F344/N hypothalami. The dose-response curves of these compounds in the former were shifted to the right and/or abolished, suggesting decreased sensitivity of LEW/N hypothalami to these neurotransmitters. The lack of difference in binding affinity and concentration of muscarinic, α1-/α2-adrenergic or 5-HT2 receptors in LEW/N and F344/N hypothalami or cerebral cortex, suggested that the impaired hypothalamic iCRH responsiveness to these neurotransmitters may relate to a faulty intracellular transducing or regulatory mechanism, which, however, apparently pertains only to CRH producing neurons. We conclude that the HPA axis of LEW/N rats is hyporesponsive to a variety of neurotransmitter stimuli and that this impairment may relate to a defective hypothalamic CRH-secreting neuron. Hence, the defect in the activation of the HPA axis in these rats is not specific to inflammatory' mediators, but rather represents a global defect in the regulation of hypothalamic CRH secretion. This is reflected also in a characteristic behavioral syndrome in the LEW/N rats, which is compatible with CRH hv-posecretion. This defect is possibly related to an alteration(s) in transduction mechanisms common to the range of neurotransmitter and inflammatory mediator stimuli studied but limited to the CRH neuron, or specifically related with the regulatory region of the CRH gene in these animals.

Original languageEnglish
Pages (from-to)600-608
Number of pages9
Issue number5
Publication statusPublished - Jan 1 1992



  • Acetylcholine
  • Corticotropin-releasing hormone
  • Fischer rats
  • Hypothalamic-pituitary-adrenal axis
  • Lewis rats
  • Norepinephrine
  • Serotonin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience

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