Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A₁ receptors

Caffeine is a commonly used drug that increases arousal, a condition associated with increased cholinergic activity in the mammalian cerebral cortex including the hippocampus. We have used the technique of microdialysis in association with microbore high-performance liquid chromatography to investigate the effects of caffeine on the extracellular levels of acetylcholine in the hippocampus of awake, freely moving rats. The oral administration of caffeine dose-dependently (3-30 mg/kg) increased the extracellular levels of acetylcholine. This increase was completely blocked when the microdialysis probe was perfused with the Na⁺-channel blocker tetrodotoxin, and strongly attenuated when a Ca²⁺-free Ringer solution was used. The effect of caffeine on hippocampal acetylcholine release was concentration-dependently counteracted by local perfusion of an A₁ receptor agonist, N⁶-cyclopentyladenosine (0.1-1 μmol/liter), but not by the A₂ receptor agonist, CGS 21680 (10 μmol/liter). Neither agonist affected base- line acetylcholine release at these concentrations. These results demonstrate that acetylcholine release in the hippocampus is under tonic inhibitory control of the endogenous neuromodulator adenosine, and that orally administered caffeine enhances action potential-dependent vesicular acetylcholine release by antagonism of local A₁ receptors. Hence, the data provide a possible link between adenosine A₁ receptors in the hippocampus, increased cholinergic activity and the psychostimulant effects of caffeine.