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

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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

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Slc6a4Ratbehavioral response to cocaine  IMP  RGD 
Slc6a4Ratconditioned place preference  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Slc6a4Ratabnormal acquisiton of operant behavior for a cocaine reinforcer  IMP compared to wild type littermateRGD 
Slc6a4m1HubrRatabnormal acquisiton of operant behavior for a cocaine reinforcer  IMP compared to wild type littermateRGD 
WI-Slc6a4m1Hubr-/-Ratabnormal acquisiton of operant behavior for a cocaine reinforcer  IMP compared to wild type littermateRGD 
Slc6a4Ratdecreased susceptibility to induced hypothermia  IMP compared to wild type littermateRGD 
Slc6a4m1HubrRatdecreased susceptibility to induced hypothermia  IMP compared to wild type littermateRGD 
WI-Slc6a4m1Hubr-/-Ratdecreased susceptibility to induced hypothermia  IMP compared to wild type littermateRGD 
Slc6a4Ratenhanced behavioral response to cocaine  IMP  RGD 
Slc6a4m1HubrRatenhanced behavioral response to cocaine  IMP compared to wild type littermateRGD 
WI-Slc6a4m1Hubr-/-Ratenhanced behavioral response to cocaine  IMP compared to wild type littermateRGD 
Slc6a4Ratenhanced conditioned place preference behavior  IMP compared to wild type littermateRGD 
Slc6a4m1HubrRatenhanced conditioned place preference behavior  IMP compared to wild type littermateRGD 
WI-Slc6a4m1Hubr-/-Ratenhanced conditioned place preference behavior  IMP compared to wild type littermateRGD 
Slc6a4Ratincreased response to stress-induced hyperthermia  IMP  RGD 
Slc6a4m1HubrRatincreased response to stress-induced hyperthermia  IMP  RGD 
WI-Slc6a4m1Hubr-/-Ratincreased response to stress-induced hyperthermia  IMP  RGD 
Slc6a4Ratinduced hyperactivity inducesIMPcocainecompared to wild type littermateRGD 
Slc6a4m1HubrRatinduced hyperactivity inducesIMPcocainecompared to wild type littermateRGD 
WI-Slc6a4m1Hubr-/-Ratinduced hyperactivity inducesIMPcocainecompared 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