Inhalant abuse is a rapidly growing health problem particularly among children and adolescents. Yet we know surprisingly little about the neural mechanisms underlying abuse liability of inhalants particularly when compared to other drugs of abuse. Specifically, knowledge of the relationship between their regional brain pharmacokinetics and features classically associated with drugs of abuse is lacking The importance of this problem and the lack of information places a sense of urgency on understanding the interactions of these volatile substances with the brain and other organs in living systems. Here we propose a systematic study of the brain and body distribution and pharmacokinetics of volatile substances (VSs) of abuse using positron emission tomography (PET). Within this context there are two specific aims; (1) To develop efficient synthesis, purification and formulation methodology of carbon-11 and fluorine-18 labeled compounds representing five important classes of abused inhalants; (2) To characterize and compare across classes of compounds regional brain and whole body distribution, absolute uptake, and pharmacokinetics of radiolabeled inhalants using PET in anesthetized baboons and ex vivo methods and microPEl technology in rodents. We will test the hypothesis that the differences in profiles of behavioral effects among individual vapors seen in animals and in their abuse potential or nature of intoxicating and toxic effects in humans are related to the diversity in their chemical structures and regional pharmacokinetics. PET is an ideal scientific tool for investigating the brain and whole body uptake as well as regional CNS distribution and clearance of labeled compounds. Moreover, recent PET studies in our laboratory using carbon-11 labeled toluene (the most widely abused inhalant) support the value of this approach to advance our understanding of the processes responsible for both addictive and toxic effects of abused inhalants. More importantly, these studies will provide the strategy and tools to identify characteristics of inhalants that are associated with their abuse liability.
