[H-3]8-OH-DPAT labels a 5-HT site coupled to inhibition of phosphoinositide hydrolysis in the dorsal raphe

The present study was undertaken to compare the properties of the [H-3]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) binding site in the dorsal raphe nucleus with the hippocampal 5-HT1A receptor. In both tissues inclusion of 1 mM Mg2+ enhanced specific [H-3]8-OH-DPAT binding, while 1 mM GTP decreased radioligand binding. [H-3]8-OH-DPAT appears to bind to a single population of binding sites in both the hippocampus and the dorsal raphe nucleus, although the K-d for the radioligand at the dorsal raphe site was five times that observed at the hippocampal 5-HT1A receptor. Similarly, although 5-HT and selective 5-HT1A receptor ligands displayed high affinity for the [3H]8-OH-DPAT binding site in the dorsal raphe nucleus, the affinity at the dorsal raphe site was less than that observed at the hippocampal 5-HT1A receptor. 8-OH-DPAT inhibited forskolin-stimulated adenylyl cyclase activity in the hippocampus, but did not alter enzyme activity in the dorsal raphe nucleus. Conversely, 8-OH-DPAT inhibited the accumulation of [H-3]inositol phosphates in the dorsal raphe nucleus, but not in the hippocampus. An inhibition of phosphoinositide hydrolysis in the dorsal raphe nucleus also was found with the putative 5-HT1A receptor selective ligands, flesinoxan and gepirone. However, addition of another putative 5-HT1A receptor selective ligand, buspirone, did not alter the generation of [3H]inositol phosphates, but blocked the inhibitory effect of 8-OH-DPAT on phosphoinositide hydrolysis. These studies demonstrate that the 8-OH-DPAT binding site in the dorsal raphe nucleus displays a binding profile which is similar to the hippocampal 5-HT1A receptor, but unlike this 5-HT1A receptor the binding site in the dorsal raphe nucleus is negatively coupled to phosphoinositide turnover. (C) 1997 Elsevier Science B.V.