• 8-SPT;
  • α-flupenthixol;
  • locomotor;
  • mice;
  • SCH23390


Caffeine is widely consumed throughout the world, but little is known about the mechanisms underlying its rewarding and aversive properties. We show that pharmacological antagonism of dopamine not only blocks conditioned place aversion to caffeine, but also reveals dopamine blockade-induced conditioned place preferences. These aversive effects are mediated by the dopamine D2 receptor, as knockout mice showed conditioned place preferences in response to doses of caffeine that C57Bl/6 mice found aversive. Furthermore, these aversive responses appear to be centrally mediated, as a quaternary analog of caffeine failed to produce conditioned place aversion. Although the adenosine A2A receptor is important for caffeine’s physiological effects, this receptor seems only to modulate the appetitive and aversive effects of caffeine. A2A receptor knockout mice showed stronger dopamine-dependent aversive responses to caffeine than did C57Bl/6 mice, which partially obscured the dopamine-independent and A2A receptor-independent preferences. Additionally, the A1 receptor, alone or in combination with the A2A 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. These data provide 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.