Identification of presynaptic serotonin autoreceptors using a new ligand: ³H-PAT

Abstract

Binding studies with appropriate labelled ligands have revealed the existence of two types of serotonin (5-HT) receptor, 5-HT₁ and 5-HT₂, in the central nervous system of mammals¹. The 5-HT₁ type is characterized by a higher affinity for agonists than for antagonists, whereas the 5-HT₂ type binds preferentially to antagonists. However, neither of these receptor types apparently corresponds to the presynaptic autoreceptor controlling 5-HT release². In an attempt to identify the presynaptic autoreceptor directly, we synthesized the tritiated derivative of 8-hydroxy-2-(di-n-propylamino) tetralin (PAT), a new tetralin derivative with potent 5-HT agonist properties³ and carried out binding studies with rat brain membranes. As we report here, in the hippocampus, the properties of ³H-PAT binding sites correspond closely to those of 5-HT₁ sites. In contrast, in the striatum, ³H-PAT binding sites exhibit a subcellular distribution and pharmacological characteristics usually associated with presynaptic autoreceptors. Furthermore, a marked loss of ³H-PAT binding sites occurs in the striatum (but not in the hippocampus) after the selective degeneration of serotoninergic fibres in 5,7-hydroxytryptamine (5,7-HT)-treated rats. Conversely, the sprouting of additional 5-HT terminals in the brain stem of adult rats treated at birth with 5,7-HT is associated with an increased density of ³H-PAT binding sites in this region. ³H-PAT thus seems to be a useful ligand for studying the biochemical and pharmacological characteristics of presynaptic autoreceptors in selected regions of rat brain.