Serotonergic inhibition of the mossy fibre--granule cell glutamate transmission in rat cerebellar slices.
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)
Thellung
S
S
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Genova, Italy.
Barzizza
A
A
Maura
G
G
Raiteri
M
M
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000502:physiology; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D009412:Nerve Fibers / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D000662:Amphetamines; D011810:Quinoxalines; D017470:Receptors, Glutamate; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D013779:Tetrodotoxin; D008719:Methiothepin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D007650:Ketanserin; D000242:Cyclic AMP; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D011188:Potassium