Norepinephrine is known to inhibit its own release from presynaptic nerve terminals through alpha 2-adrenergic receptors, which presumably have a presynaptic localization. alpha 2-Adrenergic receptors (as determined by [3H]clonidine binding) appear in rat submandibular gland membranes following reserpine treatment. These alpha 2 receptors seem to be localized postsynaptically, based on the following evidence. (1) Partial destruction of the presynaptic nerve terminals with 6- hydroxydopamine did not decrease the density of alpha 2-adrenergic receptors following subsequent reserpine administration. (2) Duct ligation, which results in atrophy of the gland, markedly decreased the density of the receptors following subsequent reserpine administration. (3) Surgical denervation resulted in the appearance of high levels of alpha 2-adrenergic receptors. (4) The changes in alpha 2 receptors paralleled the changes in postsynaptic beta-adrenergic receptor binding (as determined by [3H]dihydroalprenolol). While these results establish the existence of postsynaptic alpha 2-adrenergic receptors in an innervated tissue, the concomitant presence of a low density of presynaptic alpha 2 receptors has not been eliminated.