Inhibitory presynaptic 5-hydroxytryptamine(2A) receptors regulate evoked glutamate release from rat cerebellar mossy fibers

We studied the pharmacological characterization of the 5-hydroxytryptamine( 2) (5-HT2) heteroreceptor located on glutamatergic cerebellar mossy fiber n erve terminals. Depolarization-evoked overflow of endogenous glutamate from rat cerebellar "giant" mossy fiber synaptosomes was inhibited by 5-HT or ( +/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)-DOI], exhibiting pD(2) (= -log EC50) values of 7.37 and 7.29, respectively. Trazodone inhibi ted the depolarization-evoked glutamate overflow, exhibiting lower potency (pD(2) = 6.42) and lower efficacy with respect to 5-HT or (+/-)-DOI (maxima l inhibition, 54%, compared with 70% for either 5-HT or (+/-)-DOI). Ketanse rin, a 5-HT2A/5-HT2C receptor antagonist, counteracted the inhibitory effec t of (+/-)-DOI or trazodone. Inhibition of glutamate overflow by 5-HT, (+/- )-DOI, or trazodone was prevented by the selective 5-HT2A receptor antagoni st R-(+)-alpha-(2,3-dimethyoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperid ine-methanol (MDL 100907), while the potent and selective 5-HT2C receptor a ntagonist 6-chloro-5-methyl-1- [6-(methylpyridin-3-yloxy)pyridin-3yl-carbam oyl] indoline (SB 242084) was ineffective. In cerebellar slices, MDL 100907 increased on its own the K+-evoked release of glutamate. It is concluded t hat the evoked release of glutamate from cerebellar mossy fibers can be con trolled by inhibitory presynaptic 5-HT2A heteroreceptors, the receptors can be activated by endogenously released 5-HT, and trazodone behaves as a par tial agonist at these receptors.