Date of Award
Doctor of Philosophy (PhD)
Administration of the gut peptide, cholecystokinin (CCK), results in a suppression of meal size. The opiate-antagonist, naloxone (Nx), also suppresses feeding. With few exceptions, studies of the effect of either CCK or Nx have not examined the effects of repeated administrations, and thus there are little data concerning tolerance.
Experiment 1 was designed to investigate the effect of CCK following repeated daily injections. It was found that after several days of CCK, it no longer suppressed feeding; that is, tolerance to CCK had occurred. The demonstration of contingent tolerance in Experiment 2 confirms the results of Experiment 1 as well as the results obtained from Bednarz, Asin and Nadzan (1992), who showed that tolerance to CCK was dependent upon CCK and food being given at the same time. The results from Experiment 2 also demonstrate the importance of learning principles in mediating this tolerance; following a saline test, an over-consumption of sucrose was evident.
Experiments 3 and 4 extend these findings by demonstrating further, the importance of learning principles. Experiment 3 demonstrated that tolerance is only displayed when the drug is administered in the context of usual drug-predictive cues. Experiment 4, a latent inhibition experiment, assessed the prediction that pre-exposure to a conditioned stimulus (CS) should slow tolerance development. By demonstrating latent inhibition, this confirms the importance of learning principles.
Experiments 5 through 8 were designed to investigate tolerance to Nx. The importance of learning principles in mediating this tolerance was also assessed. Experiment 5 demonstrated that a dose of 1 mg/kg of Nx significantly decreased sucrose consumption. This suppression of intake diminishes, when animals were injected daily, as shown in Experiment 6. Experiment 7 showed that, like CCK, a contingency between food and Nx is necessary for tolerance to be demonstrated. The importance of learning principles was clearly shown in Experiment 8, where it was demonstrated that tolerance is only displayed when the drug is administered in the context of usual drug-predictive cues.
Much evidence suggests that CCK acts as an opiate-antagonist in the modulation of pain, and that Nx and CCK affect feeding in a similar manner. Experiments 1 through 8 show that tolerance to the meal-suppressive effect occurs when either CCK or Nx is given repeatedly. In a final experiment (Experiment 9), cross-tolerance to CCK- and Nx-induced meal suppression was assessed. Experiment 9 demonstrated that the tolerance that develops to CCK is symmetrical with respect to Nx. This result adds further support to the claim that CCK and Nx affect feeding behaviour in a similar manner. The mechanism(s) of action responsible for tolerance remains to be elucidated.
Girolametto-Goodison, Tina Maria, "Pavlovian Conditioning and Tolerance to Cholecystokinni-8 and Naloxone-Induced Meal Suppression" (1994). Open Access Dissertations and Theses. Paper 3084.