Inescapable shock induces resistance to the effects of dexamethasone.
Administration of bacterial endotoxin (lipopolysachharide; LPS) elevates proinflammatory cytokines, such as interleukin-1beta (IL-1beta) and IL-6, and activates the hypothalamic-pituitary-adrenal (HPA) axis. Corticosterone (CORT), the glucocorticoid (GC) effector hormone of the HPA axis in rats, inhibits both proinflammatory cytokine production/release and activity of the HPA axis itself. Exposure to chronic or repeated stressors often induces resistance to the effects of GCs. The following experiments were conducted to test the hypothesis that an acute stressor, inescapable tailshock (IS), alters responsivity of the HPA axis and proinflammatory cytokine system to dexamethasone (DEX), a synthetic GC. First, we examined the ability of various doses of DEX to suppress proinflammatory cytokine and HPA activity in response to LPS challenge 24 h after either home cage (HCC) or IS treatment. Upon finding resistance to DEX in IS animals, we examined the duration of the altered response to DEX by testing animals 1, 4 and 21 days after IS. To test whether IS animals were selectively resistant to the suppressive effects of DEX on the response to LPS, the ability of DEX to suppress HPA activity in response to a non-inflammatory stressor, exposure to an elevated "pedestal", was assessed. Again, DEX resistance was observed in IS animals. Finally, we examined whether changes in the responsivity to DEX were dependent upon the controllability of the stressor. The induction of DEX resistance was independent of the degree of behavioral control that the animal had over the stressor. Thus, a single session of IS induces DEX resistance of both HPA axis and cytokine responses measured in vivo.
O'Connor
K A
KA
Department of Psychology & Center for Neuroscience, University of Colorado, Boulder, CO 80309-0345, USA. koconnor@psych.colorado.edu
Johnson
J D
JD
Hammack
S E
SE
Brooks
L M
LM
Spencer
R L
RL
Watkins
L R
LR
Maier
S F
SF
D000222:Adaptation, Physiological / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology; D005938:Glucocorticoids / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D015213:Neuroimmunomodulation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000503:physiopathology*
D016207:Cytokines; D005938:Glucocorticoids; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone