This is an R21 proposal to investigate the physiological mechanisms of tolerance development to nitrous oxide (N2O)-induced hypothermia. Influential theories of drug tolerance contend that CNS-mediated drug-opposing responses underlie the etiology of drug tolerance and dependence. Evidence for such responses is primarily based on the observation of withdrawal effects when the drug is discontinued (or antagonized) as well as on the elicitation of the responses by conditioned stimuli. This proposal uses a novel approach for measuring these responses directly, while the drug is present, during both an initial drug administration as well as over repeated administrations. This research will also determine bow individual differences in the identity, latency and/or intensity of these responses are related to individual differences in initial sensitivity and acute tolerance to N2O hypothermia. Using a rat model that combines direct and indirect calorimetry with implanted temperature sensors, synchronous measures of core temperature and the dynamic processes of metabolic heat production and heat loss will be made during a steady-state administration of 60 percent N20. In an initial experiment, experimental (N2O) and control (placebo gas) rats will receive a 5-hour gas exposure during which core temperature and the components of heat balance are measured. The same rats will be retested 2 weeks later to determine the reliability of the mechanisms that determine core temperature. In a second experiment, individual rats given an initial N2O exposure will be classed as: a) insensitive to N2O-induced hypothermia, b) sensitive to N2O-induced hypothermia and develop acute tolerance, or c) sensitive to N2O-induced hypothermia with little or no acute tolerance. Rats in each group will be randomly assigned to receive either N2O or placebo during three additional five-hour gas exposures at one-week intervals to determine how the physiological responses controlling heat balance change as chronic tolerance develops. These studies have theoretical importance for understanding the mechanisms of drug tolerance and will begin to suggest the physiological basis of individual differences in vulnerability to addiction and drug abuse.
