Most drugs which humans abuse serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug-seeking and drug-taking behavior in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Currently, studies are focusing on cocaine, methamphetamine and nicotine. In one series of studies, we have shown that combining two discriminative stimuli associated with the same reinforcer increases responding for that reinforcer by 2-3 fold, regardless of whether the reinforcer was food, water, shock- avoidance or cocaine. Combining stimuli associated with two different appetitive reinforcers, such as food and water, also increases responding, although not to the same degree. We have recently shown a similar effect with cocaine self-administration, where combining stimuli associated with cocaine and food reinforcement led to increased responding. These results support the hypothesis that the effects of two stimuli associated with reinforcers from the same incentive class (appetitive) are mutually enhancing. Thus, in some situations a stimulus associated with an alternative reinforcer might increase the motivation to self-administer cocaine. In another series of studies, we are assessing neuroadaptive changes that follow chronic methamphetamine self-administration by rats by evaluating densities of dopamine uptake sites and D1 and D2 receptors, as well as uptake and receptor sites for other neurotransmitter systems, at various times after ceasing access to methamphetamine. Findings support the hypothesis of a functional reduction of dopaminergic neurotransmission during chronic methamphetamine exposure, unmasked when methamphetamine is withdrawn, and indicate involvement of opioid and serotonergic systems. In yet other studies, we are evaluating the range of conditions under which i.v. nicotine maintains self-administration by monkeys and how such behavior is influenced by exposure to other drugs such as caffeine. Finally, complex second-order schedules of i.v. drug injection in which long chains of behavior are maintained by highly infrequent injections of drug are being used to study motivational properties of stimuli associated with drugs such as cocaine or methamphetamine. Since second-order schedules are analogous in many ways to human drug-seeking behavior and may provide a relatively uncontaminated measure of phenomena such as "drug craving," using these procedures to evaluate pharmacological and behavioral means of reducing drug-seeking behavior will also have important implications for prevention of HIV transmission related to drug abuse.