The modulation of alpha 2-adrenoceptors by neuropeptide Y Y1 and neuropeptide Y Y2 receptor subtypes has been studied in the nucleus tractus solitarii of the male rat. The autoradiographical experiments showed that neuropeptide Y-(1-36), neuropeptide Y-(13-36), a selective neuropeptide Y Y2 receptor agonist, and [Leu31,Pro34]neuropeptide Y, a selective neuropeptide Y Y1 receptor agonist, in the nanomolar range increased the Kd value of the [3H]p-aminoclonidine binding sites in the above rank order of potency without changing the Bmax values. In contrast, in the competition experiments, the neuropeptide Y Y1 and the neuropeptide Y Y2 receptor agonists decreased and increased, respectively, with the same potency the IC50 value of l-adrenaline and especially of clonidine for the alpha 2-adrenoceptor agonist binding sites associated with an increase and a decrease of the B0 value, respectively. Cardiovascular experiments showed that microinjections of clonidine into the nucleus tractus solitarii induced dose-dependent vasodepressor and bradycardiac responses. Threshold doses for vasodepressor effects of neuropeptide Y-(1-36) and of the neuropeptide Y Y1 receptor agonist and for vasopressor effects of the neuropeptide Y Y2 receptor agonist significantly counteracted the vasodepressor action elicited by an ED50 dose of clonidine in the nucleus tractus solitarii, the bradycardiac action of clonidine also being counteracted by the neuropeptide Y Y2 but not the neuropeptide Y Y1 receptor agonist. The present results give indications for the existence of an antagonistic modulation of high affinity alpha 2-adrenoceptors by the neuropeptide Y Y1 and neuropeptide Y Y2 receptor subtype in the nucleus tractus solitarii which may contribute to a reduction of alpha 2-adrenoceptor-mediated cardiovascular depression.