Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats.
BACKGROUND
While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood.


OBJECTIVE
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.


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.


CONCLUSIONS
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.
Homberg
Judith R
JR
Hubrecht Institute, Uppsalalaan 8, 3584, CT, Utrecht, The Netherlands.
De Boer
Sietse F
SF
Raasø
Halfdan S
HS
Olivier
Jocelien D A
JD
Verheul
Mark
M
Ronken
Eric
E
Cools
Alexander R
AR
Ellenbroek
Bart A
BA
Schoffelmeer
Anton N M
AN
Vanderschuren
Louk J M J
LJ
De Vries
Taco J
TJ
Cuppen
Edwin
E
D000818:Animals; D001345:Autoradiography; D002755:Choice Behavior / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects; D055786:Gene Knockout Techniques; D005838:Genotype; D007262:Infusions, Intravenous; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*; D012646:Self Administration; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012931:Social Environment
D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D044282:Receptor, Serotonin, 5-HT1A; D003042:Cocaine