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Caffeine is widely consumed throughout the world, yet little is known about the mechanisms underlying its rewarding and aversive properties. We show that pharmacological antagonism of dopamine not only blocks conditioned place aversions to caffeine, but reveals dopamine blockadeinduced conditioned place preferences. These aversions are mediated by the dopamine D 2 receptor since knockout mice showed conditioned place preferences to doses of caffeine that C57Bl/6 mice found aversive. Further, these aversions appear to be centrally-mediated since a quaternary analogue to caffeine failed to produce conditioned place aversions. While the adenosine A 2A receptor is important for caffeine's physiological effects, this receptor seems only to modulate the appetitive and aversive effects of caffeine. A 2A receptor knockout mice showed stronger dopamine-dependent aversions to caffeine than C57Bl/6 animals, which partially obscured the dopamine-and A 2A receptor-independent preferences. Additionally, the A 1 receptor, alone or in combination with the A 2A receptor, does not seem to be important for caffeine's rewarding or aversive effects. Finally, excitotoxic lesions of the tegmental pedunculopontine nucleus revealed that this brain region is not involved in dopamine blockade-induced caffeine reward. This data provides surprising new information on the mechanism of action of caffeine, indicating that adenosine receptors do not mediate caffeine's appetitive and aversive effects. We show that caffeine has an atypical reward mechanism, independent of the dopaminergic system and the tegmental pedunculopontine nucleus and provide additional evidence in support of a role for the dopaminergic system in aversive learning.

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