Neurochemical profile of eltoprazine.
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.
Schipper
J
J
Department of Pharmacology, Duphar B.V., Weesp, The Netherlands.
Tulp
M T
MT
Sijbesma
H
H
D000818:Animals; D001665:Binding Sites; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D003342:Corpus Striatum / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000737:chemistry; D018377:Neurotransmitter Agents / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology; D015290:Second Messenger Systems; D012701:Serotonin / Q000378:metabolism / Q000493:pharmacokinetics / Q000502:physiology; D012702:Serotonin Antagonists; D013552:Swine; D014018:Tissue Distribution; D014316:Tritium
D015306:Biogenic Monoamines; D018377:Neurotransmitter Agents; D010716:Phosphatidylinositols; D010879:Piperazines; D011619:Psychotropic Drugs; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014316:Tritium; D012701:Serotonin; C063828:eltoprazine