The behavioral pharmacological profile of a drug in a pertinent species is necessary for evaluating quantitatively not only how the drug functions as a reinforcer but also 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. 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. In a recently completed series of experiments we have demonstrated that there are qualitative differences in behavioral response to psychomotor stimulant drugs which result from chronic exposure to caffeine which depend on the level of caffeine exposure. We varied caffeine concentration, using lower levels of caffeine exposure than in previous studies. Our results clearly indicate that the dose of caffeine is a very important (or, the main) variable which determines this differential strength. Thus, chronic exposure to a very low dose of caffeine in rats (a concentration of caffeine of 0.25 mg/ml in the drinking water), potentiated the motor-activating and discriminative-stimulus effects of systemic administrations of amphetamine, cocaine and nicotine, and was not associated with the development of tolerance to the motor-activating effects of caffeine. On the other hand, an intermediate dose of caffeine (1.0 mg/ml in the drinking water), did not potentiate either the motor-activating or the discriminative-stimulus effects of amphetamine, cocaine or nicotine, and, in fact, was associated with the development of complete and insurmountable tolerance to the motor-activating effects of caffeine. In recently completed in vivo microdialysis experiments, we found that chronic caffeine exposure also enhances the increases in extracellular concentration of dopamine in the shell of the nucleus accumbens induced by nicotine and methamphetamine. These findings provide experimental evidence to support some epidemiological data which suggest that chronic caffeine exposure can alter behavioral responses to the psychostimulants amphetamine, cocaine and nicotine In another series of experiments, the serotonergic component of the subjective response to methamphetamine has been extensively characterized in our laboratory using two-lever choice, drug-discrimination procedures. We have demonstrated that stimulation of the serotonergic system contributes to methamphetamine's discriminative-stimulus effects. These effects appear to be mediated through 5-HT release and blockade of reuptake and subsequent activation of 5-HT2A/2C receptors, with a limited involvement of other 5-HT receptor subtypes; the 5-HT2A/2C agonist DOI produced a left-ward shift of the methamphetamine dose-response curve that was reversed by ketanserin, an antagonist at 5-HT2A/2C receptors. Ketanserin also reversed the left-ward shift in the methamphetamine dose-response curve induced by fluoxetine, a 5-HT uptake inhibitor, suggesting that 5-HT2A/2C receptors play, at the least, a modulatory role in the behavioral actions of methamphetamine. This is in agreement with neurochemical studies showing that 5-HT2A/2C antagonists can reverse some of the effects of amphetamine, serotonin and dopamine agonists on the dopaminergic system and can partially reverse some changes in brain neurochemistry induced by neurotoxic doses of methamphetamine. It, however, remains to be determined whether these effects are mediated directly through 5-HT stimulation or indirectly through the modulation of dopaminergic neurotransmission.
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