The influence of intrahippocampal injections of glutamate receptor agonists on neuropeptide Y (NPY) mRNA expression was investigated in granule cells and interneurons of the rat dentate gyrus. One day after local injection of non-neurodegenerative doses (20 and 70 nmol) of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)ACPD], NPY mRNA levels were more than doubled in ipsilateral granule cells and interneurons. Doses of 200 and 400 nmol caused up to 15.9-and 4.6-fold mRNA increases in granule cells and interneurons, respectively. The group I metabotropic glutamate receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG; 50 nmol), but not the group III receptor agonist L(؉)-2-amino-4-phosphonobutyrate (L-AP4; 20 and 200 nmol) exerted a similar action. The general metabotropic glutamate receptor antagonist (؉)-␣-methyl-4-carboxyphenylglycine (MCPG; 200 nmol), the group I receptor antagonist (S)-4-carboxyphenylglycine (4-CPG; 200 nmol) and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (1 mg/kg; i.p.) partially blocked the (1S,3R)-1aminocyclopentane-1,3-dicarboxylate-induced increase in NPY mRNA in granule cells, but not in interneurons. (S)-4-carboxyphenylglycine (200 nmol) by itself increased NPY mRNA levels in ipsilateral interneurons threefold, indicating the activation of phospholipase D coupled receptors. Non-neurodegenerative doses of (RS)-␣-amino-3-hydroxy-5-methyl-4isoxazolepropionate (AMPA, 0.3 nmol) caused modest increases in NPY mRNA levels in ipsilateral interneurons, whereas neurodegenerative doses (1-10 nmol) induced markedly increased NPY mRNA levels in granule cells (up to 11-fold) and interneurons (up to threefold). It is suggested that activation of metabotropic glutamate receptors stimulates NPY mRNA expression in granule cells and interneurons in the rat dentate gyrus. Whereas in granule cells NPY mRNA upregulation is preferentially mediated by group I metabotropic glutamate receptors, it may involve ionotropic and metabotropic glutamate receptors in interneurons.