Effects of adenosine receptor subtypes on hippocampal extracellular serotonin level and serotonin reuptake activity.

To clarify the effects of adenosine receptor subtypes (A 1 , A 2 , and A3) on hippocampal serotoninergic function, hippocampal extracellular serotonin (5-HT) levels were determined by in vivo microdialysis in freely moving rats under various conditions. Both adenosine and an adenosine A 1 receptor agonist, 2-chloro-N6-cyclopentyladenosine, decreased extracellular 5-HT levels, whereas an adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), and caffeine increased these levels. A selective A 2A receptor agonist (CGS-21680), an adenosine A 2 receptor agonist (PD-125944), an adenosine A 2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), and an adenosine A3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA), did not affect extracellular 5-HT levels. When the adenosine A 1 receptor was blocked by CPT, the hippocampal extracellular 5-HT level was increased by adenosine, CGS-21680, and PD-125944, and decreased by caffeine, DMPX, and APNEA. When both adenosine A 1 and A 2 receptors were blocked by CPT and DMPX, the extracellular 5-HT level was decreased by adenosine, caffeine, and APNEA. The hippocampal extracellular 5-HT level was not affected by administration of APNEA alone, but was decreased by this agent when the adenosine A 1 receptor was blocked, irrespective of whether the adenosine A 2 receptor was functional. These inhibitory effects of adenosine, caffeine, and APNEA on extracellular 5-HT levels, during both adenosine A 1 and A 2 receptor blockade, were inhibited by selective 5-HT reuptake inhibitors. These results indicate that the stimulatory effects of the adenosine A 2 receptor and the inhibitory effects of the A3 receptor on hippocampal extracellular 5-HT levels are masked by the inhibitory effects of the adenosine A 1 receptor.