Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT 2A receptors: functional receptor-binding and in vivo electrophysiological studies

Psychopharmacology (Berl). 2007 Feb;190(3):373-82. doi: 10.1007/s00213-006-0621-y. Epub 2006 Nov 25.

Abstract

Background: Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors.

Materials and methods: This study examined aripiprazole's interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties.

Results: Aripiprazole produced increases in [(35)S]GTPgammaS binding to rat hippocampal membranes. Its potency (pEC(50) = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT(1A)-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT(1A)-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT(1A) receptors (K (i) = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT(2A) receptors (K (i) = 3.4 nM), moderate affinity to 5-HT(2C) (K (i) = 15 nM) and 5-HT(7) (K (i) = 39 nM) receptors, and low affinity to 5-HT(6) receptors (K (i) = 214 nM) and 5-HT transporter (K (i) = 98 nM). In addition, aripiprazole potently blocked 5-HT(2A)-receptor-mediated increases in intracellular Ca(2+) levels in a rat pituitary cell line (IC(50) = 11 nM).

Discussion: These results support a partial agonist activity for aripiprazole at 5-HT(1A) receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Aripiprazole
  • CHO Cells
  • Calcium / metabolism
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Electrophysiology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Male
  • Neurons / drug effects
  • Neurons / physiology
  • Piperazines / pharmacology*
  • Quinolones / pharmacology*
  • Radioligand Assay
  • Raphe Nuclei / cytology
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin Receptor Agonists / pharmacology

Substances

  • Antipsychotic Agents
  • Piperazines
  • Quinolones
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Aripiprazole
  • Calcium