Transient Adenosine Modulates Serotonin Release Indirectly in the Dorsal Raphe Nuclei

Rapid adenosine transiently regulates dopamine and glutamate via A₁ receptors, but other neurotransmitters, such as serotonin, have not been studied. In this study, we examined the rapid modulatory effect of adenosine on serotonin release in the dorsal raphe nuclei (DRN) of mouse brain slices by using fast-scan cyclic voltammetry. To mimic adenosine release during damage, a rapid microinjection of adenosine at 50 pmol was applied before electrical stimulation of serotonin release. Transient adenosine significantly reduced electrically evoked serotonin release in the first 20 s after application, but serotonin release recovered to baseline as adenosine was cleared from the slice. The continuous perfusion of adenosine did not change the evoked serotonin release. Surprisingly, the modulatory effects of adenosine were not regulated by A₁ receptors as adenosine still inhibited serotonin release in A₁KO mice and also after perfusion of an A₁ antagonist (8-cyclopentyl-1,3-dipropyl xanthine). The inhibition was also not regulated by A₃ receptors as perfusion of the A₃ antagonist (MRS 1220) in A₁KO brain slices did not eliminate the inhibitory effects of transient adenosine. In addition, adenosine also inhibited serotonin release in A_2AKO mice, showing that A_2A did not modulate serotonin. However, perfusion of a selective 5HT_1A autoreceptor antagonist drug [(S)-WAY 100135 dihydrochloride] abolished the inhibitory effect of transient adenosine on serotonin release. Thus, the transient neuromodulatory effect of adenosine on DRN serotonin release is regulated by serotonin autoreceptors and not by adenosine receptors. Rapid, transient adenosine modulation of neurotransmitters such as serotonin may have important implications for diseases such as depression and brain injury.