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, Volume 200, Issue 3, pp 367–380

First Online: 27 June 2008Received: 21 January 2008Accepted: 25 May 2008


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

ObjectivesTo 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 methodsThe 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.

ResultsCocaine-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.

ConclusionThese 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.

KeywordsKnockout rat Serotonin transporter Cocaine self-administration 5-HT1A receptor Postsynaptic Somatodendritic AbbreviationsCPPconditioned place preference


DATdopamine transporter


FRfixed ratio


NETnoradrenaline transporter

PRprogressive ratio

SERTserotonin transporter

SERThomozygous serotonin transporter knockout rat

SERTheterozygous serotonin transporter knockout rat

SERTwild-type control rat

SIHstress-induced hyperthermia

SSRIselective serotonin reuptake inhibitor


5-HTTLPRserotonin transporter-linked polymorphic region

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Autor: Judith R. Homberg - Sietse F. De Boer - Halfdan S. Raasø - Jocelien D. A. Olivier - Mark Verheul - Eric Ronken - Alex


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