The behavioral pharmacological profile of a drug in a pertinent species is necessary for evaluating quantitatively how the drug functions as a reinforcer and how use or abuse of the drug affects other aspects of the subject's behavior. Ongoing studies on the direct behavioral effects of drugs include a number of different paradigms. A variety of studies involve observations of changes in spontaneous and learned behavior following acute injections of drugs. For example, we have recently shown the female rats are much more sensitive to the locomotor activating effects of cocaine than are male rats. Similar sensitivity differences are observed following administration of the selective dopamine uptake inhibitor GBR12909 and the D1 selective agonist SKF82598 suggesting that male and female rats differ in dopamine receptor function. A wide range of other studies are ongoing to investigate pharmacological mechanisms that determine how psychoactive drugs such as nicotine, methamphetamine, and cocaine function as discriminative stimuli or effect ongoing learned behavior. In one series of studies we are using laboratory animals to characterize nicotine-caffeine interactions under conditions of chronic caffeine exposure. There is a strong positive correlation between coffee drinking and cigarette smoking and these studies are designed to determine if caffeine-nicotine interactions can be observed in animals. For these studies, rats were chronically exposed to caffeine in their drinking water. Then the behavioral response to nicotine in these caffeinated rats were compared to water-drinking rats. Our studies revealed that chronic caffeine exposure can alter the behavioral response to nicotine, and this pattern of changes both overlaps and is distinct from patterns of changes observed with amphetamine and cocaine under comparable conditons. Most importantly, we were able to characterize experimental conditions under which caffeine can potentiate the reinforcing, stimulatory and discriminative stimulus properties of nicotine. Finally, we have studied the pharmacological properties of methamphetamine discrimination and have found that although dopaminergic systems play a dominant role in methamphetamine's subjective effects, other neurotransmitter systems are involved. The serotonergic system appeared to be particularly important, with effects mediated by 5-HT1A, 5-HT2, and possibly 5-HT3 receptors, as well as serotonin uptake sites. Noradrenergic systems also appear to be involved in methamphetamine's effects, with discrimination mediated by alpha-1 and alpha-2 receptors, and norepinephrine uptake sites. Finally, we have shown that thioperamide, an H3 antagonist that elevates brain histamine levels, potentiates the discriminative-stimulus effects of methamphetamine.