Abstract
The effects of trazodone and putative sigma (σ) receptor ligands were investigated on KCl-stimulated release of glutamate (Glu) and γ-aminobutyric acid (GABA) from cerebellar mossy fibre synaptosomes. Both trazodone and serotonin (5-HT) inhibited the increase of Glu and GABA release evoked by 15 mM KCl. Trazodone increased the inhibition of Glu release caused by 0.01 μM 5-HT, while it antagonized the inhibition induced by higher 5-HT concentrations. Despite the low affinity of trazodone for both σ 1 and σ 2 binding sites, with a p K i of 5.9 and 6.0 respectively, two σ receptor ligands, (+)-3-[3-hydroxypheny]- N-(1-propyl)piperidine ((+)-3-PPP) and N-[2-(3,4-dichlorophenyl)ethyl]- N-methyl-2-(dimethylamino)ethylamine (BD 1047) antagonized the effects of trazodone. The putative σ receptor ligand N-allylnormetazocine ((+)-SKF 10,047) mimicked the inhibitory effect of trazodone. As with trazodone, (+)-3-PPP and BD 1047 antagonized the activity of (+)-SKF 10,047 but not that of 5-HT. On the whole, these results suggest that trazodone shares a common molecular target with σ compounds distinct from that of 5-HT and is involved in K +-stimulated Glu and GABA release from mossy fibre cerebellar synaptosomes.
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