Background: There are numerous studies on the effects of caffeine on memory and learning. The activation of a2-adrenoreceptors has been reported to impair memory functions in both rats and humans. In this study, interaction of a2-adrenergic system and caffeine on memory and learning was evaluated.Materials and methods: In this experimental study, 90 wistar rats assigned into six groups of fifteen. Rats received yohimbine (4, 6, 8, 10mg), as a a2-adrenergic antagonist, clonidine (2, 4, 6mg), as a a2-adrenergic agonist, and caffeine (10, 20, 30mg). The cannula was implanted into the right lateral ventricle of all rats with steriotaxi method. Then, they were trained in shuttlebox. Post-training intracerebroventricular (ICV) injection was carried out in all experiments and optimum doses were identified.Results: Caffeine and yohimbine fostered memory and learning (p<0.001), while clonidine diminished these abilities compared to saline injection (p<0.05). Co-administration of the optimum doses of clonidine and yohimbine showed statistically significant reduction in the time of step-through latency (p<0.05). Instead, co-administration of clonidine and caffeine revealed no significant increase in the time of step-through latency (NS).Conclusion: It is concluded that yohimbine and caffeine, unlike clonidine, increase memory.