Behavioral conditioning of physiological responses using pharmacologic agents as unconditioned stimuli (USC) suggests that conditioning principles can be applied to pharmacotherapeutic regimens and that behavioral responses can reflect and regulate pathophysiological processes. In previous studies, we demonstrated that the development of disease and mortality could be delayed by substituting conditioned stimuli (CSs) for active drug in the pharmacotherapy of spontaneously developing systemic lupus erythematosus in mice. Extending these and other preliminary findings, we propose to design and evaluate a regimen of pharmacotherapy structured as a series of conditioning trials to promote survival of lupus-prone mice using a fraction of the drug dose normally required to impede the progression of disease. Specifically, it is hypothesized that a partial schedule of pharmacologic reinforcement can approximate the effects of a continuous (standard) pharmacotherapeutic regimen and/or will be more resistant to extinction when drug treatment is discontinued. This will be tested by treating lupus-prone mice with a flavored drinking solution, the conditioned stimulus (CS), and cyclophosphamide, the UCS, on: (a) a continuous reinforcement schedule; (b) on a partial (50%) reinforcement schedule; and (c) on a continuous schedule but with a lower dose of drug -- a dose equal to that received by animals under a partial schedule. Control groups would receive noncontingent CS-UCS presentations or placebo. Following the common period of pharmacotherapy, groups would be subdivided into those that: (i) continue to receive CS + UCS; (ii) receive only the CS; and (iii) receive neither CS nor UCS. The hypothesis that lupus-prone mice are capable of adopting behavioral strategies that reflect and/or regulate their disease state will be evaluated in MRL-lpr/lpr (autoimmune) and MRL+/+ (control, congenic) mice. Experiments will be designed to (1) compare taste aversion learning as a function of parameters of the CS (e.g., number of conditioning trials) and UCS (dose of CY), and the stage of the disease; and (2) to determine if lupus-prone mice will voluntarily select a drinking solution that contains therapeutic doses of CY. In addition to the measurement of behavior, the development of disease and the effects of conditioning in modifying lymphadenopathy and anti-DNA antibody titers will also be determined. The results of these studies would provide dramatic evidence of the impact of behavior on pharmacotherapeutic processes and disease and for channels of communication between the central nervous system and the immune system.
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| Grota, L J; Schachtman, T R; Moynihan, J A et al. (1989) Voluntary consumption of cyclophosphamide by Mrl mice. Brain Behav Immun 3:263-73 |
| Grota, L J; Ader, R; Cohen, N (1987) Taste aversion learning in autoimmune Mrl-lpr/lpr and Mrl +/+ mice. Brain Behav Immun 1:238-50 |
