Inhibition of 5-HT neurotransmission increases clonidine protective effects on naloxone-induced conditioned place aversion in morphine-dependent rats

Neuropsychopharmacology. 2003 Feb;28(2):276-83. doi: 10.1038/sj.npp.1300033. Epub 2002 Jul 15.


Previous pharmacological studies have implicated serotonergic brain systems in opiate-withdrawal-precipitated conditioned place aversion. To assess this hypothesis, we tested the effects of either (i). a near-total 5,7-dihydroxytryptamine-induced lesion (90% depletion) or (ii). an acute serotonin (5-HT) inhibition induced by the specific stimulation of 5-HT1A autoreceptors (8-OHDPAT 5-100 microg/kg), on naloxone-induced conditioned place aversion in morphine-dependent rats. Morphine dependence was induced by the implantation of morphine slow-release pellets. The protective properties of clonidine (an alpha-2 adrenergic agonist classically given for opiate detoxification) were also tested after inhibition of 5-HT transmission. Serotonergic lesions in morphine-dependent rats failed to alter naloxone-induced conditioned place aversion but increased the sensitivity to the protective effects of clonidine. Acute neuropharmacological blockade of serotonin transmission also potentiated the clonidine effects on naloxone-induced conditioned place aversion. When combined with the 5-HT1A agonist 8-OHDPAT, clonidine was also found to be more potent. Further understanding of this serotonin/noradrenaline interaction might help devise new therapeutic treatments for the acute opiate withdrawal syndrome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology
  • Clonidine / pharmacology*
  • Conditioning, Psychological / drug effects*
  • Conditioning, Psychological / physiology
  • Dose-Response Relationship, Drug
  • Male
  • Morphine Dependence / metabolism*
  • Naloxone / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Serotonin
  • Naloxone
  • Clonidine