Advancing the Understanding of Drug-Induced Allostasis

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DESCRIPTION (provided by applicant): Chronic drug administration can produce allostasis, a maladaptive state related to drug tolerance. Repeated administrations of nitrous oxide (N2O) lead to a frank intra-administration allostatic thermoregulatory state underlain by an imbalance between body heat production and loss, but the physiologic mechanisms are uncertain. This small-grant application proposes to investigate N2O -induced allostatic changes and how individual effector systems interact to produce the 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 different from control values, potentialy 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. Our laboratory uses 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. Recent research and preliminary data from our laboratory suggest that allostasis can result when effector systems that normally adjust a regulated variable's value in opposite directions become concurrently active and work in opposition with one another. Two specific aims are proposed that will advance our understanding of drug-induced allostasis. Specific Aim 1 will develop and validate the use of infrared thermography as a continuous and non-invasive method for assessing the activity of two major effector systems for heat production and heat loss during allostasis development resulting from repeated N2O administrations. Specifically, heat production will be assessed from interscapular brown adipose tissue temperature and heat loss from the rat's tail skin temperature. Specific Aim 2 proposes to build and validate a live-in convection type direct calorimeter that will make it possible to observe core temperature, heat production and heat loss throughout long duration N2O administrations. Previous work suggests that opposing effector activity may become apparent during a prolonged initial N2O administration before allostasis is evident at the level of the regulated variable. Due to size limitations imposed by our small direct calorimeter chambers, it has not been feasible to study the dynamics of how heat production and heat loss interact during an extended steady-state N2O administration. This work has practical and theoretical importance for understanding the mechanisms underlying drug-induced allostasis and addiction. The proposed research has the added relevance of investigating an abusable inhalant which is an important, yet understudied, research area.