Chronic drug administration can produce allostasis, a maladaptive state related to drug tolerance. This proposal investigates nitrous oxide (N2O)-induced allostatic changes and the motivational consequences of being in an allostatic state. Allostasis refers to a disordered form of homeostatic regulation wherein a regulated variable, or one or more of its controlling determinants, persistently functions at levels significantly different from control values, potentially compromising an individual's health or viability. An allostatic model of drug addiction posits that biobehavioral control systems regulate variables relevant to drug taking behavior and that these control systems are vulnerable to drug-induced allostatic changes which promote the development of addiction. The proposed studies use a sophisticated experimental model that combines direct and indirect calorimetry so that core temperature and its determinants (metabolic heat production and heat release) can be simultaneously measured, enabling rigorous determination of allostatic dynamics during repeated N2O administrations. This thermoregulatory model system also provides a sensitive method for determining the motivational consequences of allostasis. Preliminary data indicate that adolescent rats are especially prone to develop drug-induced allostatic changes, suggesting that increased susceptibility to allostasis development may be a critical etiological factor for the heightened vulnerability to drug addiction during adolescence.
Specific Aim (SA) 1 compares allostasis development in adolescent versus mature rats over a range of N2O concentrations, determines whether these allostatic processes stabilize, and explores how they can be extinguished. SA 2 compares the thermally motivated effects of a range of N2O concentrations in adolescent versus mature rats and assesses the motivational effects of an allostatic state during adolescence. In addition, the relationship between initial sensitivity, allostasis development and N2O self-administration behavior will be investigated. SA 3 examines whether factors measured in the allostatic state (N2O concentration, core temperature, heat loss, heat production) can be used as predictors of motivated behavior. This work has practical and theoretical importance for understanding the mechanisms underlying drug addiction. The proposed research has the added relevance of investigating an abusable inhalant during the adolescent period which NIH has identified as an important, yet understudied, research area.

Public Health Relevance

A form of homeostatic dysregulation known as allostasis is suspected to play an etiologic role in the development of drug addiction. The proposed research uses an understudied inhalant to investigate drug-induced allostasis during a developmental period (adolescence) that is known for its heightened susceptibility to drug addiction. The findings of this research will contribute to our understanding of the pathogenesis and treatment of drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023484-04
Application #
8081097
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Noursi, Samia
Project Start
2008-09-15
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$337,066
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; Ramsay, Douglas S (2018) Concentration-related metabolic rate and behavioral thermoregulatory adaptations to serial administrations of nitrous oxide in rats. PLoS One 13:e0194794
Ramsay, Douglas S; Al-Noori, Salwa; Shao, Jason et al. (2015) Predicting addictive vulnerability: individual differences in initial responding to a drug's pharmacological effects. PLoS One 10:e0124740
Ramsay, Douglas S; Woods, Stephen C; Kaiyala, Karl J (2014) Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors. Temperature (Austin) 1:257-267
Ramsay, Douglas S; Woods, Stephen C; Kaiyala, Karl J (2014) Drug-induced regulatory overcompensation has motivational consequences: Implications for homeostatic and allostatic models of drug addiction. Temperature (Austin) 1:248-256
Kaiyala, Karl J; Woods, Stephen C; Ramsay, Douglas S (2014) Persistence of a hyperthermic sign-reversal during nitrous oxide inhalation despite cue-exposure treatment with and without a drug-onset cue. Temperature (Austin) 1:268-275
Ramsay, Douglas S; Woods, Stephen C (2014) Clarifying the roles of homeostasis and allostasis in physiological regulation. Psychol Rev 121:225-47
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
Ramsay, Douglas S; Seaman, Jana; Kaiyala, Karl J (2011) Nitrous oxide causes a regulated hypothermia: rats select a cooler ambient temperature while becoming hypothermic. Physiol Behav 103:79-85
Woods, Stephen C; Ramsay, Douglas S (2011) Food intake, metabolism and homeostasis. Physiol Behav 104:4-7
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

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