Effect of quinine on autoreceptor-regulated serotonin release in the rat hippocampus

The involvement of K+ channels in the autoregulation of terminal serotonin (5-hydroxytryptamine, 5-HT) release was investigated by microdialysis in the hippocampus of conscious rats. Extracellular 5-HT was increased concentration-dependently by the K+ channel blocker quinine (10, 100 and 1000 microM in perfusate), and tetrodotoxin (10 microM) but not fluoxetine (5 microM) exerted a partially attenuating influence. The 5-HT1/2/6 receptor antagonist methiothepin (50 microM) increased dialysate 5-HT, most likely through 5-HT1B autoreceptors tonically activated in the hippocampus of awake rats as opposed to the previously reported lack of effect 5-HT1B autoreceptor blockade in anesthetized rats. The effect of methiothepin was greatly reduced by preperfusion with quinine (100 microM), consonant with a role for quinine-sensitive K+ channels in the autoregulation of 5-HT release in the hippocampus by 5-HT receptor antagonism. In contrast, the reduction in dialysate 5-HT induced by the 5-HT1 receptor agonist RU 24969 (1 microM), in the presence of fluoxetine (5 microM), persisted in the co-presence of quinine, consonant with the involvement of (extrasynaptic?) 5-HT autoreceptors not coupled with quinine-sensitive K+ channels.