Characterization of the glutamate receptors mediating release of somatostatin from cultured hippocampal neurons.

L-Glutamate, NMDA, DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate (KA) increased the release of somatostatin-like immunoreactivity (SRIF-LI) from primary cultures of rat hippocampal neurons. In Mg2+-containing medium, the maximal effects (reached at similar to 100 mu M) amounted to 737% (KA), 722% (glutamate), 488% (NMDA), and 374% (AMPA); the apparent affinities were 22 mu M (AMPA), 39 mu M (glutamate), 41 mu M (KA), and 70 mu M (NMDA). The metabotropic receptor agonist trans-1-aminocyclopentane-1,3-dicarboxylate did not affect SRIF-LI release. The release evoked by glutamate (100 mu M) was abolished by 10 mu M dizocilpine (MK-801) plus 30 mu M 1-aminophenyl-4-methyl-7,8- methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466). Moreover, the maximal effect of glutamate was mimicked by a mixture of NMDA + AMPA. The release elicited by NMDA was sensitive to MK-801 but insensitive to GYKI 52466. The AMPA- and KA-evoked releases were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX) or by GYKI 52466 but were insensitive to MK-801. The release of SRIF-LI elicited by all four agonists was Ca2+ dependent, whereas only the NMDA-evoked release was prevented by tetrodotoxin. Removal of Mg2+ caused increase of basal SRIF-LI release, an effect abolished by MK-801. Thus, glutamate can stimulate somatostatin release through ionotropic NMDA and AMPA/KA receptors. Receptors of the KA type (AMPA insensitive) or metabotropic receptors appear not to be involved.