Psychopharmacology (2008) 200:367–380
DOI 10.1007/s00213-008-1212-x

ORIGINAL INVESTIGATION

Adaptations in pre- and postsynaptic 5-HT1A 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

Received: 21 January 2008 / Accepted: 25 May 2008 / Published online: 27 June 2008
# The Author(s) 2008

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 selfadministration. 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 selfadministration 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 5HT1A 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

J. R. Homberg : M. Verheul : E. Cuppen (*)
Hubrecht Institute,
Uppsalalaan 8,
3584 CT, Utrecht, The Netherlands e-mail: e.cuppen@niob.knaw.nl

J. R. Homberg : J. D. A. Olivier : A. R. Cools : B. A. Ellenbroek
Department of Cognitive Neuroscience,
Radboud University Nijmegen,
Nijmegen, The Netherlands

H. S. Raasø : A. N. M. Schoffelmeer : T. J. De Vries
Department of Anatomy and Neurosciences, VU Medical Center,
Amsterdam, The Netherlands
S. F. De Boer
Department of Animal Physiology, Groningen University,
Groningen, The Netherlands
L. J. M. J. Vanderschuren
Rudolf Magnus Institute of Neuroscience,
Department of Pharmacology and Anatomy,
University Medical Center Utrecht,
Utrecht, The Netherlands

E. Ronken
Solvay Pharmaceuticals Research Laboratories,
Weesp, The Netherlands

Present address:
B. A. Ellenbroek
Evotec Pharmaceutical Division, Neuropharmacology,
Hamburg, Germany

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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 5HT1A 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.
Keywords Knockout rat . Serotonin transporter . Cocaine self-administration . 5-HT1A receptor . Postsynaptic .
Somatodendritic
Abbreviations
CPP
conditioned place preference
DA
dopamine
DAT
dopamine transporter
ENU
N-ethyl-nitrosurea
FR
fixed ratio
NA
noradrenaline
NET
noradrenaline transporter
PR
progressive ratio
SERT
serotonin transporter
−/−
SERT homozygous serotonin transporter knockout rat SERT+/− heterozygous serotonin transporter knockout rat SERT+/+ wild-type control rat
SIH
stress-induced