Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice

Naunyn Schmiedebergs Arch Pharmacol. 2004 Jun;369(6):547-53. doi: 10.1007/s00210-004-0939-0. Epub 2004 May 25.

Abstract

Receptor antagonist and knockout studies have demonstrated that blockade of signalling via nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) has antidepressant-like effects in mice submitted to the forced swimming test (FST). The aim of the present study was to explore further the antidepressant-like properties of the NOP antagonist UFP-101 in different species (mouse and rat) and using different assays [FST and tail suspension test (TST)], and to investigate the mechanism(s) involved in its actions.UFP-101 (10 nmol i.c.v.) reduced immobility time of Swiss mice in the TST (mean+/-SEM) from 179+/-11 to 111+/-10 s. N/OFQ (1 nmol i.c.v.) was without effect per se, but fully prevented the effect of UFP-101. The spontaneous immobility time of NOP(-/-) CD1-C57BL/6J-129 mice in the TST was much lower than that of wild-type (NOP(+/+)) littermates (75+/-11 vs. 144+/-17 s) or of Swiss mice. UFP-101 (10 nmol i.c.v.) decreased immobility time (-65%) and increased climbing time (71%) in rats submitted to the FST. In rat brain slices, N/OFQ (100 nM) triggered robust K(+)-dependent hyperpolarizing currents in locus coeruleus and dorsal raphe neurons. UFP-101 (3 microM) fully prevented N/OFQ-induced currents, but was inactive per se. Fluoxetine, desipramine (both 30 mg/kg i.p.) and UFP-101 (10 nmol i.c.v.) reduced immobility time of mice in the FST. The serotonin synthesis inhibitor p-chlorophenylalanine methylester (PCPA, 4 x 100 mg/kg per day i.p.) prevented the antidepressant-like effects of fluoxetine and UFP-101 (but not desipramine), whereas N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4, neurotoxic for noradrenergic neurons; 50 mg/kg i.p., 7 days beforehand), suppressed only the effect of desipramine. Neither pretreatment affected spontaneous immobility time per se.Thus, UFP-101 exhibits pronounced antidepressant-like effects in different species and animal models, possibly by preventing the inhibitory effects of endogenous N/OFQ on brain monoaminergic (in particular serotonergic) neurotransmission. Participation of the N/OFQ-NOP receptor system in mood modulation sets new potential targets for antidepressant drug development.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain / drug effects
  • Brain / physiology
  • Electrophysiology
  • Hindlimb Suspension / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Narcotic Antagonists*
  • Opioid Peptides / pharmacology*
  • Rats
  • Receptors, Opioid / agonists
  • Receptors, Opioid / genetics
  • Signal Transduction / drug effects
  • Swimming / physiology

Substances

  • (Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)
  • Antidepressive Agents
  • Narcotic Antagonists
  • Opioid Peptides
  • Receptors, Opioid
  • nociceptin
  • nociceptin receptor