RGD Reference Report - Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

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

Authors: Homberg, JR  De Boer, SF  Raaso, HS  Olivier, JD  Verheul, M  Ronken, E  Cools, AR  Ellenbroek, BA  Schoffelmeer, AN  Vanderschuren, LJ  De Vries, TJ  Cuppen, E 
Citation: Homberg JR, etal., Psychopharmacology (Berl). 2008 Oct;200(3):367-80. Epub 2008 Jun 27.
RGD ID: 4889490
Pubmed: PMID:18581099   (View Abstract at PubMed)
DOI: DOI:10.1007/s00213-008-1212-x   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
behavioral response to cocaine  IMP 4889490 RGD 
conditioned place preference  IMP 4889490 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal acquisiton of operant behavior for a cocaine reinforcer  IMP 4889490; 4889490; 4889490compared to wild type littermateRGD 
decreased susceptibility to induced hypothermia  IMP 4889490; 4889490; 4889490compared to wild type littermateRGD 
enhanced behavioral response to cocaine  IMP 4889490 RGD 
enhanced behavioral response to cocaine  IMP 4889490; 4889490compared to wild type littermateRGD 
enhanced conditioned place preference behavior  IMP 4889490; 4889490; 4889490compared to wild type littermateRGD 
increased response to stress-induced hyperthermia  IMP 4889490; 4889490; 4889490 RGD 
induced hyperactivity inducesIMPcocaine4889490; 4889490; 4889490compared to wild type littermateRGD 
Objects Annotated

Genes (Rattus norvegicus)
Slc6a4  (solute carrier family 6 member 4)
Slc6a4m1Hubr  (solute carrier family 6 member 4; ZFN induced mutant1, Hubr)

Strains
WI-Slc6a4m1Hubr-/-  (NA)


Additional Information