Biochemical and radiohistochemical methods were used to study alterations in alpha-2 adrenergic receptors in the kindling model of epilepsy. The radioligands used for antagonist and agonist binding were [3H]idazoxan and [3H]p-aminoclonidine, respectively. Radioligand binding to membranes isolated from eight brain regions disclosed a small (14%) but statistically significant reduction in [3H]idazoxan binding in a single area, amygdala-pyriform-entorhinal cortex. This was confirmed by a larger (25%) reduction (P less than .02) in agonist binding in the same region. These reductions were present in animals sacrificed 1 day, but not 2 weeks, after the last kindled seizure. Quantitative radiohistochemical studies identified a bilaterally symmetric reduction of approximately 20% of [3H]p-aminoclonidine binding in the pyriform cortex and the central, medial and lateral amygdaloid nuclei. No significant differences were detected in nine other structures. We propose that the reduction in alpha-2 receptor binding contributes in part to the reduced sensitivity of pyriform cortex neurons of kindled animals to the inhibitory effects of alpha 2 agonists. The reduced alpha-2-receptor binding may also underlie a transient attenuation of alpha-2 receptor-mediated neuro-transmission and thereby constitute one mechanism contributing to kindling development.