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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016047-04
Application #
7214652
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Hoffman, Allison
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$287,488
Indirect Cost
Name
University of Washington
Department
Dentistry
Type
Schools of Dentistry
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kaiyala, Karl J; Chan, Ben; Ramsay, Douglas S (2012) Robust thermoregulatory overcompensation, rather than tolerance, develops with serial administrations of 70% nitrous oxide to rats. J Therm Biol 37:30-40
Kaiyala, Karl J; Ramsay, Douglas S (2011) Direct animal calorimetry, the underused gold standard for quantifying the fire of life. Comp Biochem Physiol A Mol Integr Physiol 158:252-64
Woods, Stephen C; Ramsay, Douglas S (2007) Homeostasis: beyond Curt Richter. Appetite 49:388-98
Kaiyala, Karl J; Butt, Shehzad; Ramsay, Douglas S (2007) Systems-level adaptations explain chronic tolerance development to nitrous oxide hypothermia in young and mature rats. Psychopharmacology (Berl) 191:233-42
Kaiyala, Karl J; Butt, Shezhad; Ramsay, Douglas S (2007) Direct evidence for systems-level modulation of initial drug (in)sensitivity in rats. Psychopharmacology (Berl) 191:243-51
Ramsay, Douglas S; Kaiyala, Karl J; Leroux, Brian G et al. (2005) Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats. Psychopharmacology (Berl) 181:48-59
Kaiyala, Karl J; Ramsay, Douglas S (2005) Assessment of heat production, heat loss, and core temperature during nitrous oxide exposure: a new paradigm for studying drug effects and opponent responses. Am J Physiol Regul Integr Comp Physiol 288:R692-701