Excitatory amino acids (EAAs) are known to stimulate neurohormone release through the activation of ion-channel-linked receptors (ionotropic receptors). Here we report that a receptor for EAAs linked to polyphosphoinositide hydrolysis (metabotropic receptor) is also present at the hypothalamus where its expression is developmentally regulated. Stimulation of [3H]inositolmonophosphate ([3H]InsP) formation by quisqualate (EC50 = 1.5 microM), ibotenate (EC50 = 100 microM) and trans-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD; EC50 = 30 microM) is extremely high (up to 50-fold) in the first 10 days of postnatal life, progressively declines during maturation and is virtually absent in the adult. Stimulation of phosphoinositide hydrolysis by quisqualate, ibotenate and t-ACPD is more pronounced than that induced by classical neurotransmitters that stimulate inositol phosphate formation such as norepinephrine and carbamylcholine. Agonists of the ionotropic glutamate receptor such as kainate, NMDA and alpha-amino-3-hydroxy-5-methyl-5-isoxazolpropionate (AMPA), do not modify inositol phosphate accumulation in hypothalamic slices. The selective antagonist of quisqualate metabotropic receptor, D,L-2-amino-3-phosphonopropionate (AP3), produces a slight stimulation of phosphoinositide hydrolysis, but potently antagonizes the stimulation produced by quisqualate and t-ACPD.