Corpora amylacea (CA) have an affinity to nucleic acids as shown by in situ hybridization experiments. However, little is known about the specificity of this interaction, as well as the mechanism involved. We investigated the ability of different probes of digoxigenin-labeled oligonucleotides corresponding to some specific neuronal receptors, both sense and antisense, to bind to CA from human autopsy brain tissue. The bound nucleotides were detected with antidigoxigenin antibody and the signal was further amplified using the tyramide signal amplification system. The affinity of binding varies with the sequence of nucleotides. The most intense signal is produced by the adenosine-2A receptor antisense probe and the least intense signal is produced by the N-methyl-D-aspartate receptor sense probe. The affinity of binding for the same probe does not depend on the localization of CA in the central nervous system. Complete staining loss by proteinase K pretreatment in higher concentrations shows that the binding motif is partially proteinaceous. The circumferential but not the punctate internal staining is diminished by mild amylglucosidase pretreatment, suggesting a process of progressive apposition and condensation.