Inhalant abuse is a major social and medical problem in the United States and has been characterized as the predominant drug abuse problem in some developing countries. Despite this, less is know about the cellular actions of inhalants which produce their behavioral effects than for virtually any other major drug of abuse. One method that has been extremely valuable for exploring the cellular mechanisms underlying the behavioral effects of abused drugs is the drug discrimination procedure. The discriminative stimulus effects of drugs in animals are thought to model subjective effects in humans. For technical reasons, the examination of the discriminative stimulus effects of abused inhalants has been limited to testing these inhalants in animals trained to discriminate other injected drugs. While these methods have proven useful in suggesting that abused inhalants may have complex actions at multiple neurotransmitter receptor systems including, GABAA and NMDA receptors, a more direct approach is needed. Recently we have developed a novel procedure in which mice can readily be trained to discriminate the subjective effects of inhaled volatile compounds themselves. Our preliminary studies with a prototypic abused inhalant, toluene, suggest that its interoceptive CMS effects are sufficient to produce full substitution to the inhaled toluene cue. With the major technical challenges overcome, the first specific aim of this proposal is do a more parametric characterization of the speed of onset and duration of the discriminative stimulus effects of inhaled toluene. The second specific aim is to compare and contrast the discriminative stimulus effects of inhaled toluene to other abused inhalants, volatile anesthetics and gasses. This will allow abused inhalants, which are otherwise difficult to categorize given their wide diversity, to be categorized according to their degree of similarity to toluene. The final specific aim is to determine the cellular sites of action that underlie the interoceptive stimulus effects of toluene and a second abused inhalant 1,1,1-trichloroethane. These studies should greatly enhance our understanding of how abused inhalants act at the receptor level to produce their behavioral actions and may provide important insights useful for the development of selective treatments for inhalant abuse.
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