Serotonergic inhibition of the mossy fibre?granule cell glutamate transmission in rat cerebellar slices

Abstract

The glutamatergic mossy fibre-->granule cell pathway has been investigated in rat cerebellar slices. Exposure to 35 mM KCl, a concentration of K+ known to elicit Ca(2+)-dependent releases of excitatory amino acids from cerebellar slices, raised cGMP levels. The cGMP response was decreased in a concentration-dependent manner by D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) indicating the involvement of ionotropic glutamate receptors of both the N-methyl-D-aspartate (NMDA) and the non-NMDA type. The K(+)-evoked production of cGMP was potently inhibited (EC50 = 1.21 nM) by 1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI), a selective 5-HT2 receptor agonist. The effect of DOI (0.01 microM) was antagonized by 0.03 microM of the 5-HT2 receptor antagonists ketanserin and methiothepin. At concentrations higher than 0.1 microM, both antagonists increased on their own the cGMP response elicited by high-K+. This effect was insensitive to tetrodotoxin. It had been previously shown that rat mossy fibre endings release glutamate upon depolarization and that such release can be inhibited by activation of 5-HT2 receptors sited on the mossy fibre endings. Altogether the available data suggest the following conclusions: a) the glutamate/aspartate endogenously released in cerebellar slices during K+ depolarization increase cGMP synthesis through the activation of both NMDA and non-NMDA receptors; b) a portion of the cGMP response can be prevented by 5-HT2 receptor activation and may reflect the activity of the mossy fibre--granule cell pathway.(ABSTRACT TRUNCATED AT 250 WORDS)