Susceptibility to Autoimmune Disease and Drug Addiction in Inbred Rats: Are There Mechanistic Factors in Common Related to Abnormalities in Hypothalamic‐Pituitary‐Adrenal Axis and Stress Response Function?

Abstract

A BSTRACT : DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental autoimmune diseases. These diseases include rheumatoid arthritis models such as collagen-induced arthritis (CIA) and adjuvantinduced arthritis (AIA), multiple sclerosis models such as myelin-basic-protein (MBP)-induced experimental autoimmune encephalomyelitis (MBP-EAE), and autoimmune uveitis models such as retinal S antigen (SAG) and interphotoreceptor-retinoid-binding-protein (IRBP) -induced experimental autoimmune uveitis (SAG-EAU and IRBP-EAU, respectively). DA and LEW rats are also addiction-prone to various drugs of abuse, such as cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction. By contrast, F344 and BN rats show quite different phenotypes. They are relatively resistant to CIA, AIA, MBP-EAE, SAG-EAU, and IRBP-EAU, and they are relatively resistant to addiction. Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function. For example, circadian production of corticosteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in corticosterone levels. Since corticosteroids potentially have significant influences on immune function and autoimmune disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect genetic control of these various phenotypic differences, focusing initially on the regulation of autoimmune disease expression. Using genomewide scanning techniques involving F2 crosses of DA ؋ F344 (CIA and AIA), DA ؋ BN (CIA), and LEW ؋ F344 [IRBP-EAU and streptococcal-cell-wall arthritis (SCWA)], we have d Address for correspondence: Ronald L. Wilder, M.D., Ph.D., Chief, Inflammatory Joint Diseases Section, ARB, NIAMS, NIH, Bldg. 10, Room 9N240, Bethesda, Maryland 20892. Voice: 301-496-6499; fax: 301-402-0012. wilderr@exchange.nih.gov 785 WILDER et al. : AUTOIMMUNE DISEASE & DRUG ADDICTION identified, to date, 14 genomic regions [quantitative trait loci (QTL)] that regulate disease expression in these crosses. Development and analysis of QTLcongenic rats involving these loci are in progress and should permit us to address the relationships among autoimmune disease susceptibility, drug addiction, and HPA axis and stress response function. These initial data, however, indicate that the genetic control of the autoimmune disease traits is highly complex.

Circadian rhythms on hypothalamic–pituitary–adrenal axis hormones and cytokines of collagen induced arthritis in rats

“…The defective response of the neuroendocrine system to inflammatory stimuli suggests a non-MHC genetic factor contributing to the pathogenesis of RA [7]. Some experimental models such as adjuvant-induced arthritis (AA) [8] and inbred Lewis (LEW/N) rats to group A streptococcal cell wall peptidoglycan polysaccharide (SCW) arthritis are also related to defective HPA axis responsiveness to inflammatory mediators [9].…”

Endocrine Perturbation Increases Susceptibility of Mice to Anthrax Lethal Toxin

“…Hyper-HPA axis and GC responsiveness have been associated with resistance to inflammatory disease, while a blunted HPA axis and GC response are associated with greater susceptibility to some autoimmune/ inflammatory diseases (8,40,41,59). BALB/c mice and Fischer rats are hyper-GC responsive and resistant to inflammatory disease compared to hypo-HPA-responsive C57BL/6 mice or Lewis rats (2,3,8,37,38,40,41,59). Interruption of the GC response by adrenalectomy (ADX) or with a GR antagonist (RU486) enhances the inflammatory responses through inhibition of GR-mediated cytokine gene repression and increases mortality in otherwise inflammation-resistant hosts.…”

Microarray profile analysis of toxic cocaine‐induced alterations in the expression of mouse brain gene sequences: a possible ‘protective’ effect of buprenorphine

“…cocaine addiction (Holz et al, 2000;Wilder et al, 2000). The expression of a part of the MOR (mu opioid receptor) gene, a gene related to the BUP targets (Jones and Ross, 1995), also tended to be increased (RT = 2.53, DF = 1) but modification of expression of this brain-region-specific gene was small compared with other genes.…”