Adaptations in pre- and postsynaptic 5-HT(1A) receptor function and cocaine supersensitivity in serotonin transporter knockout rats

Judith R Homberg, Sietse F De Boer, Halfdan S Raasø, Jocelien D A Olivier, Mark Verheul, Eric Ronken, Alexander R Cools, Bart A Ellenbroek, Anton N M Schoffelmeer, Louk J M J Vanderschuren, Taco J De Vries, Edwin Cuppen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

79 Citations (Scopus)

Abstract

RATIONALE: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood.

OBJECTIVES: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout (SERT-/-) rat and the involvement of compensatory changes in 5-HT1A receptor function are the objectives of the study.

MATERIALS AND METHODS: The SERT-/- rat was tested for cocaine-induced locomotor activity, cocaine-induced conditioned place preference, and intravenous cocaine self-administration. In addition, the function and expression of 5-HT1A receptors was assessed using telemetry and autoradiography, respectively, and the effect of 5-HT1A receptor ligands on cocaine's psychomotor effects were studied.

RESULTS: Cocaine-induced hyperactivity and conditioned place preference, as well as intravenous cocaine self-administration were enhanced in SERT-/- rats. Furthermore, SERT-/- rats displayed a reduced hypothermic response to the 5-HT1A receptor agonist 8-OHDPAT. S-15535, a selective somatodendritic 5-HT1A receptor agonist, reduced stress-induced hyperthermia (SIH) in wild-type controls (SERT+/+), while it increased SIH in SERT-/- rats. As 5-HT1A receptor binding was reduced in selective brain regions, these thermal responses may be indicative for desensitized 5-HT1A receptors. We further found that both 8-OHDPAT and S-15535 pretreatment increased low-dose cocaine-induced locomotor activity in SERT-/- rats, but not SERT+/+ rats. At a high cocaine dose, only SERT+/+ animals responded to 8-OHDPAT and S-15535.

CONCLUSION: These data indicate that SERT-/- -associated 5-HT1A receptor adaptations facilitate low-dose cocaine effects and attenuate high-dose cocaine effects in cocaine supersensitive animals. The role of postsynaptic and somatodendritic 5-HT1A receptors is discussed.

Original languageEnglish
Pages (from-to)367-380
Number of pages14
JournalPsychopharmacology
Volume200
Issue number3
DOIs
Publication statusPublished - Oct-2008

Keywords

  • knockout rat
  • serotonin transporter
  • cocaine self-administration
  • 5-HT(1A) receptor
  • postsynaptic
  • somatodendritic
  • CONDITIONED PLACE PREFERENCE
  • IN-VIVO MICRODIALYSIS
  • DORSAL RAPHE NUCLEUS
  • SEEKING BEHAVIOR
  • MICE LACKING
  • 8-OH-DPAT-INDUCED HYPOTHERMIA
  • PSYCHOSTIMULANT ADDICTION
  • LOCOMOTOR-ACTIVITY
  • SUCROSE-SEEKING
  • DOPAMINE

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