Inhalant abuse, which includes the general anesthetic gas, nitrous oxide (N2O), has continued to increase since 1975, as determined by two epidemiological databases, the National High School Senior Survey and the National Household Survey on Drug Abuse. The problem of inhalant abuse is worldwide and is not necessarily limited to any particular age group or socioeconomic group. Therefore, understanding the variables which influence the behavioral effects of N2O, especially its reinforcing effects, and understanding the neurochemical substrates of the actions of the drug, continue to be imperative. In past studies, we have examined modulating factors of the reinforcing effects of N2O in healthy volunteers, and we will continue to do so in the present application. In the first series of studies, we will examine the impact of alcohol consumption (light vs. moderate), pain threshold (low vs. high), behavioral contingencies (relax vs. work on tasks), and concomitant administration of other drugs (alcohol, amphetamine) on the reinforcing effects of extended (30 min) inhalation of N2O. In addition, we will examine the reinforcing effects of bolus concentrations of N2O - single breath inhalations is a common way that N2O is used in recreational settings. A key component to many of these studies in the first series is that in a matter of several sessions, we will be able to assess the subjective and reinforcing effects of a full range of subanesthetic doses of N2O - this is normally not possible when assessing other CNS drugs with abuse liability due to their longer acting effects. In the second series of studies, we will investigate possible neurochemical mechanisms that mediate the different effects of N2O, including its analgesic, subjective and psychomotor effects. By using the appropriate drug receptor antagonists, we will focus on those systems which have been implicated as crucial in mediating N2O's effects in animal studies - the opioidergic, GABAergic, and dopaminergic systems. Through these studies, we will continue to gain a better understanding of a drug that falls into a class of abused drugs (inhalants), whose behavioral actions and neurochemical mechanisms related to abuse potential need to be more fully delineated and characterized.
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