Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats

Psychopharmacology (Berl). 2008 Oct;200(3):367-80. doi: 10.1007/s00213-008-1212-x. Epub 2008 Jun 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoradiography
  • Choice Behavior / drug effects
  • Cocaine / administration & dosage
  • Cocaine / pharmacology
  • Cocaine-Related Disorders / genetics*
  • Cocaine-Related Disorders / psychology
  • Conditioning, Operant / drug effects
  • Gene Knockout Techniques*
  • Genotype
  • Infusions, Intravenous
  • Motivation*
  • Motor Activity / drug effects
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / genetics*
  • Self Administration
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Social Environment


  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, rat
  • Receptor, Serotonin, 5-HT1A
  • Cocaine