Characterization of a [³H]-5-hydroxytryptamine binding site in rabbit caudate nucleus that differs from the 5-HT_1A, 5-HT_1B, 5-HT_1C and 5-HT_1D subtypes

[³H]5-HT binding sites were analyzed in membranes prepared from the rabbit caudate nucleus (CN). [³H]5-HT labeled both 5-HT_1A and 5-HT_1C recognition sites, defined by nanomolar affinity for 8-OH-DPAT and mesulergine respectively; however, these represented only a fraction of total specific [³H]5-HT binding. Saturation experiments of [³H]5-HT binding in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine to block 5-HT_1A and 5-HT_1C sites revealed that non-5-HT_1A/non-5-HT_1C sites represented about 60% of the total 5-HT₁ sites and that they exhibited saturable, high affinity, and homogeneous binding. The pharmacological profile of the non-5-HT_1A/non-5-HT_1C sites (designated 5-HT_1R) also differed from that of 5-HT_1B and 5-HT₂ sites, but was similar to that of the 5-HT_1D site. However, significant differences existed between the 5-HT_1R and 5-HT_1R sites for their K_i values for spiperone, spirilene (an analog of spiperone), metergoline, and methiothepin. The study of modulatory agents (calcium and GTP) also showed differences between the 5-HT_1R and 5-HT_1D sites. For example, the effects of GTP on agonist binding to the 5-HT_1R sites were less than on the 5-HT_1D sites in bovine caudate. In addition, calcium enhanced the effects of GTP on the 5-HT_1R sites, whereas calcium inhibited the GTP effect on the 5-HT_1D sites. The present findings demonstrate the presence of a high-affinity [³H]5-HT binding site in rabbit CN, designated 5-HT_1R, that is different from previously defined 5-HT_1A, 5-HT_1B, 5-HT_1C, 5-HT_1D, and 5-HT₂ sites.