The Pavlovian conditioning of IL-1-induced glucocorticoid secretion.

Recombinant IL-1-beta, which is capable of stimulating the pituitary-adrenal axis to secrete corticosterone, was paired with environmental cues in either a taste aversion or odor conditioning procedure. Among mice receiving paired delivery of cues and IL-1, subsequent re-exposure to cues elicited corticosterone production. This response was significantly greater than in animals that were conditioned but not re-exposed to the cues or were exposed to the cues alone. These results indicate that the IL-1 activation of adrenal cortical secretion can be conditioned to environmental stimuli.

Conditioned tolerance to drug-induced (poly I:C) natural killer cell activation: effects of drug-dosage and context-specificity parameters.

Three experiments were conducted to evaluate the role of drug-dosage and stimulus-specificity parameters on the tolerance of drug-induced (poly I:C) natural killer (NK) cell activity. In the first experiment a protocol which provided mice with four weekly 20 micrograms/mouse ip injections of the immunostimulatory synthetic polynucleotide (poly I:C) following exposure to either a simple odor cue or a complex cue resulted in tolerance of NK cell activity. The identical protocol with a higher drug dose (50 micrograms/mouse) did not produce tolerance. In a second experiment, the stimulus specificity of tolerance was assessed by giving two groups of mice repeated signaled drug injections. For one of these groups the final poly I:C injection of the series was signaled, while for the other group it was not. Although both groups were tolerant relative to controls not previously exposed to the drug, indirect evidence of conditioning was obtained. Specifically, it was found that tolerance among mice receiving the signal on the test was such that they were not different from undrugged controls, while uncued mice had significantly higher levels of NK cell activity. The third experiment evaluated the role of stimulus specificity within an extinction paradigm. It was found that tolerance was reversed in mice provided with repeated nonreinforced reexposure to drug-signaling cues, while mice exposed to novel cues remained tolerant. These results further support the hypothesis that associative factors contribute to the tolerance of a drug-induced immune response.

Tolerance to drug-induced (poly I:C) natural killer cell activation: congruence with a Pavlovian conditioning model.

Two experiments were conducted to assess the role of conditioning factors on the tolerance of drug-induced natural killer (NK) cell activity. A protocol in which mice were given four weekly injections of the immunostimulatory synthetic polynucleotide (poly I:C) paired with a complex environmental stimulus produced a reliable tolerance effect. The sensitivity of the observed tolerance to known decremental conditioning procedures--extinction (Experiment 1) and preexposure to the conditioning stimulus (latent inhibition, Experiment 2)--was investigated. The results indicated that posttreatment exposure to drug-signaling cues (i.e., extinction) significantly reversed tolerance such that NK cell activity was at a level comparable to that for controls receiving the drug for the first time (Experiment 1). In a similar fashion, pretreatment exposure to the drug-signaling cues (CS preexposure) inhibited the development of tolerance (Experiment 2). These results provide initial evidence that nonpharmacological manipulations of drug-signaling environmental cues can affect tolerance to the immunostimulatory effect of poly I:C, as would be expected with a conditioning analysis of such tolerance.