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J Pharmacol Exp Ther. 2000 Dec;295(3):1101-11.

Changes in the ambulatory activity and discriminative stimulus effects of psychostimulant drugs in rats chronically exposed to caffeine: effect of caffeine dose.

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Preclinical Pharmacology Laboratory, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA.


Caffeine is a common psychoactive constituent of coffee, carbonated beverages, and over-the-counter medications. This study examined the effects of chronic caffeine exposure on the behavioral response to acute administrations of psychostimulant drugs on ambulatory activity and on the pharmacological characteristics of nicotine discrimination in rats. Rats were maintained continuously on caffeine added to the drinking water at a concentration of 0.25 or 1. 0 mg/ml that resulted in plasma caffeine concentrations ranging from 0.37 to 5.95 microg/ml. Rats maintained on tap water served as control groups. Exposure to the lower caffeine concentration (0.25 mg/ml) potentiated stimulatory effects of nicotine, amphetamine, and cocaine on ambulatory activity and failed to produce tolerance to the acute stimulatory effects of caffeine. In contrast, exposure to the higher caffeine concentration (1.0 mg/ml) did not alter the effects of the psychomotor stimulants on ambulatory behaviors but resulted in the development of complete, insurmountable tolerance to the acute stimulatory effects of caffeine. In the nicotine discrimination paradigm (0.4 mg/kg, training dose, a fixed-ratio 10 schedule of food delivery in a two-lever choice paradigm), rats exposed to the lower, but not to the higher, caffeine concentration acquired the nicotine discrimination significantly faster and were more sensitive to the effects of amphetamine and cocaine in substitution tests than water-drinking rats. Caffeine exposure did not change pharmacokinetic properties of nicotine (i.e., plasma levels, metabolism). In summary, exposure to two different caffeine solutions within a range of plasma levels observed in humans resulted in quantitatively distinct changes in psychostimulant-induced nonoperant and operant measures of behavior. These results suggest that dietary consumption of moderate doses of caffeine may be associated with enhanced reactions to some psychostimulants.

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