Eltoprazine, a drug which reduces aggressive behaviour, binds selectively to 5-HT1 receptor sites in the rat brain: an autoradiographic study

Eltoprazine, a phenylpiperazine derivative, selectively reduces offensive aggression in animal models. The present study was designed to localize and characterize the binding sites of [3H]eltoprazine in the rat brain and to compare the distribution of these sites with the distribution of [3H]5-HT binding sites. The binding of [3H]eltoprazine to whole tissue sections was saturable and revealed an apparent dissociation constant (Kd) of 11 nM. Autoradiographic studies demonstrated a widespread distribution of [3H]eltoprazine binding sites throughout the brain. Specific [3H]eltoprazine binding was completely displaced by 5-HT; conversely, unlabelled eltoprazine reduced [3H]5-HT binding to the levels of non-specific binding. The overall distribution of [3H]eltoprazine binding sites showed a strong resemblance to the location of 5-HT1 binding sites labelled with [3H]5-HT. Yet, regions enriched in 5-HT1A and 5-HT1C sites (e.g. dentate gyrus and choroid plexus, respectively) revealed relatively more [3H]5-HT binding as compared to [3H]eltoprazine binding, whereas [3H]eltoprazine binding was more pronounced in 5-HT1B receptor dense areas such as the dorsal subiculum, substantia nigra, ventral pallidum and globus pallidus. Displacement of [3H]eltoprazine with various selective serotonergic drugs demonstrated binding of [3H]eltoprazine to 5-HT1 receptor subtypes. The pharmacological and anatomical data indicate that eltoprazine binds to 5-HT1A, 5-HT1B and to a lesser extent to 5-HT1C binding sites in the rat brain. These results emphasize the important role of serotonin in the regulation of offensive aggression and suggest that eltoprazine may serve as a new tool to study the involvement of central 5-HT1 receptors in the expression of this behaviour.