Neurochemical Profile of Eltoprazine

Drug Metabol Drug Interact. 1990;8(1-2):85-114. doi: 10.1515/dmdi.1990.8.1-2.85.

Abstract

In this paper we present the neurochemical profile of eltoprazine, a drug that specifically inhibits offensive aggression. Eltoprazine interacts selectively with serotonin (5-HT) receptor subtypes (Ki-values for 5-HT1A, 5-HT1B and 5-HT1C receptors are 40, 52 and 81 nM respectively). Affinity for other neurotransmitter receptors is much lower (Ki-values greater than 400 nM) than for 5-HT1 receptors. The selective interaction with 5-HT1 receptor subtypes is confirmed by in vitro autoradiographic studies using radiolabelled eltoprazine. The overall distribution of [3H]eltoprazine bears a strong resemblance to the localization of 5-HT1 binding sites labelled by [3H]5-HT, although some differences are observed. Eltoprazine (1 microM) inhibits the forskolin stimulated c-AMP production in hippocampus slices of the rat, indicating an agonistic action on the 5-HT1A receptor. The K+ stimulated release of 5-HT from rat cortex slices is inhibited by eltoprazine (pD2 = 7.8). The maximal response, however, was clearly less than that of the full agonist 5-HT, indicating partial agonistic activity on the 5-HT1B receptor (alpha = 0.5). Eltoprazine has a weak antagonistic action (IC50 = 7 microM) on the 5-HT1C receptor as revealed by inhibition of the 5-HT-induced accumulation of inositol phosphates in the choroid plexus of the pig. In vivo, eltoprazine reduces 5-HIAA levels in the striatum, without affecting the 5-HT levels. Eltoprazine also reduces the 5-HT synthesis rate as shown by 5-HTP accumulation after decarboxylase inhibition. These data indicate that eltoprazine acts as a 5-HT agonist in vivo in a dose range that affects aggressive behaviour (0.3-3 mg/kg p.o.). Taken together from a variety of neurochemical studies there is strong evidence both in vitro and in vivo that the pharmacological actions of eltoprazine can be attributed to an interaction with the 5-HT system, most probably via a (partial) agonistic action on 5-HT1A and 5-HT1B receptors.

MeSH terms

  • Animals
  • Binding Sites
  • Biogenic Monoamines / metabolism
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / ultrastructure
  • Corpus Striatum / metabolism
  • Male
  • Neurons / chemistry
  • Neurotransmitter Agents / physiology
  • Phosphatidylinositols / metabolism
  • Piperazines / metabolism
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Psychotropic Drugs / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin / physiology
  • Second Messenger Systems
  • Serotonin / metabolism
  • Serotonin / pharmacokinetics
  • Serotonin / physiology
  • Serotonin Antagonists
  • Swine
  • Tissue Distribution
  • Tritium

Substances

  • Biogenic Monoamines
  • Neurotransmitter Agents
  • Phosphatidylinositols
  • Piperazines
  • Psychotropic Drugs
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Tritium
  • Serotonin
  • eltoprazine