Abstract

We studied the pharmacological characterization of the 5-hydroxytryptamine₂ (5-HT₂) heteroreceptor located on glutamatergic cerebellar mossy fiber nerve 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 pD₂ (= −log EC₅₀) values of 7.37 and 7.29, respectively. Trazodone inhibited the depolarization-evoked glutamate overflow, exhibiting lower potency (pD₂ = 6.42) and lower efficacy with respect to 5-HT or (±)-DOI (maximal inhibition, 54%, compared with 70% for either 5-HT or (±)-DOI). Ketanserin, a 5-HT_2A/5-HT_2C receptor antagonist, counteracted the inhibitory effect of (±)-DOI or trazodone. Inhibition of glutamate overflow by 5-HT, (±)-DOI, or trazodone was prevented by the selective 5-HT_2A receptor antagonistR-(+)-α-(2,3-dimethyoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidine-methanol (MDL 100907), while the potent and selective 5-HT_2Creceptor antagonist 6-chloro-5-methyl-1-[6-(methylpyridin-3-yloxy)pyridin-3yl-carbamoyl] indoline (SB 242084) was ineffective. In cerebellar slices, MDL 100907 increased on its own the K⁺-evoked release of glutamate. It is concluded that the evoked release of glutamate from cerebellar mossy fibers can be controlled by inhibitory presynaptic 5-HT_2Aheteroreceptors, the receptors can be activated by endogenously released 5-HT, and trazodone behaves as a partial agonist at these receptors.