Caffeine Functions by Inhibiting Dorsal and Ventral Hippocampal Adenosine 2A Receptors to Modulate Memory and Anxiety, Respectively

As a nonspecific antagonist of the adenosine A receptor (A R), caffeine enhances learning and improves memory impairment. Simultaneously, the consumption of caffeine correlates with a feeling of anxiety. The hippocampus is functionally differentiated along its dorsal/ventral axis and plays a crucial role both in memory and anxiety. Whether caffeine exerts its regulation by inhibiting A Rs in different subregions of the hippocampus is still unknown. In the present study, we found that after chronic intake of drinking water containing caffeine (1 g/L, 3 weeks), mice exhibited aggravated anxiety-like behavior and enhanced memory function. Tissue-specific, functional disruption of dorsal hippocampal A Rs by the CRE-LoxP system prevented the memory-enhancing effect of caffeine, while selective disruption of ventral hippocampal A Rs blocked the impact of caffeine on anxiety. These results, together with the enhanced memory of dorsal hippocampus A R knockout mice and greater anxiety-like behavior of ventral hippocampus A R knockout mice without caffeine, indicates a dissociation between the roles of ventral and dorsal hippocampal A receptors in caffeine's effects on anxiety-like and memory-related behavioral measures, respectively. Furthermore, optogenetic activation of dorsal or ventral hippocampal A Rs reversed the behavioral alterations caused by drinking caffeine, leading to impaired memory or decreased anxiety-like behaviors, respectively. Taken together, our findings suggest that the memory- and anxiety-enhancing effects of caffeine are related to the differential effects of inhibiting A Rs in the dorsal and ventral hippocampus, respectively.