Our objective is to advance the behavioral pharmacology and toxicology of abused inhalants. We will further develop self- administration models that, in conjunction with studies of learned and unlearned behavior, will: provide a method to assess abuse potential; assist in setting workplace exposure limit values to prevent substance abuse and performance impairment; determine whether inhalants maintain """"""""drug-seeking"""""""" behavior as strongly as other abused drugs; measure the severity of dependence, withdrawal, and toxicity syndromes; assess irritancy and its consequences; and characterize direct behavioral effects of solvents. Inhalants self-administration by the monkey. Primates are required for this effort because attempts to generate rodent models have not succeeded. The alkyl benzenes comprise 30 to 40 of gasoline, which is abused by inhalation, and are present in glues, paint thinner, and solvents; concentration-effect curves will be determined for alkyl benzenes to assess structure-activity relationship and to provide comparisons with effects on conditioned and unconditioned performance in primate, rat and mouse. Examining schedules of reinforcement will determine the effectiveness of these agents as reinforcers, and permit comparison with other reinforcers. Blood levels will be determined. The abuse potential of alkyl nitrates will be characterized. Aversive properties. Initial aversiveness may play an important role in determining abuse potential. Techniques to make inhalants aversive are of paramount importance, and could influence product formulation. We intend to study physiological affects associated with brief or low-level exposures to upper airway irritants in primates during self-administration and conditioned performance studies. Performance effects. In the rate, conditioned behaviors are more sensitive than unconditioned behavior, and m-xylene is more potent than the less lipophilic toluene. In the mouse, however, the solvents are qualitatively different, and the order of potency reversed; m-xylene is more irritating, and the mouse more sensitive to irritants. The rate apparently is more sensitive than humans, so primate experiments are necessary for extrapolation. We will relate concentrations that are reinforcing to those that alter behavior. Exploring structure-activity relationships and species differences may help estimate both performance impairment potency and abuse potential, will help characterize the pharmacologic profile of inhalants and, with self-administration and pharmacokinetic data, helps us to understand the determinants of inhalant abuse, thus facilitating prevention and intervention strategies.
