The proposed research investigates individual differences in the physiological mechanisms mediating tolerance to nitrous oxide (N20)-induced hypothermia. Drug tolerance, dependence and withdrawal are thought to be manifestations of a common underlying """"""""adaptive"""""""" response that develops with repeated drug use. By combining direct and indirect calorimetry with implanted telemetric temperature assessment, core temperature and its determinants (metabolic heat production and heat release) can be measured synchronously during steady-state administrations of N2O. With this approach, drug-effect opposing adaptive responses can be measured directly during both an initial drug exposure and over repeated administrations while tolerance develops. The experimental design will also allow determination of the role of Pavlovian drug conditioning in the development of tolerance. Experiment #1 will determine an optimal N2O concentration for use as an interoceptive drug cue. Experiment #2 will use a conditioning paradigm in which rats are given sessions during which one stimulus (CS+) is always associated with N2O and a second stimulus (CS-) is always associated with placebo gas. Tolerance and its conditioned correlates will be assessed by dissociating the CS from the drug being administered for some rats. Experiment #3 will use a similar paradigm with rats that differ in initial sensitivity and acute tolerance development during an initial exposure to N2O. Preliminary data indicate that these individual differences on the first drug exposure will predict how an individual reacts over repeated drug administrations. Specifically, individual differences in the """"""""adaptive"""""""" changes that occur during an initial N2O exposure will be manifest as differences in the degree to which tolerance develops and more specifically to the conditioned responses that the animal learns over repeated drug administrations. c-Fos immunoreactivity (a marker of neuronal activity) will be measured in specified brain areas in Experiments 2 and 3 to begin identification of the neural substrates underlying tolerance and its associated conditioned responses. These studies have theoretical importance for understanding the mechanisms of drug tolerance as well as what accounts for individual differences in vulnerability to addiction and drug abuse. In addition, these studies will integrate basic science inhalant research within the broader context of addiction research.
