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Serotonin confessions of a dirty drug: dissecting the role of the serotonin transporter in cocaine action using SERT I172M mice (848.5)
Author(s) -
Simmler Linda,
Nackenoff Alexander,
Stutz Sonja,
Anastasio Noelle,
Cunningham Kathryn,
Blakely Randy
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.848.5
Subject(s) - serotonin transporter , pharmacology , serotonin , conditioned place preference , reuptake , mdma , reuptake inhibitor , dopamine , dopamine transporter , norepinephrine transporter , chemistry , transporter , antagonism , serotonin uptake inhibitors , amphetamine , antidepressant , addiction , dopamine uptake inhibitors , potency , psychology , medicine , fluoxetine , neuroscience , nucleus accumbens , receptor , biochemistry , in vitro , hippocampus , gene
Dopamine (DA) reuptake blockade is primary for the neuroplasticities that lead to cocaine addiction. However, cocaine is well known to inhibit the serotonin (5‐HT), DA, and norepinephrine transporters at relatively equivalent potencies. To elucidate the role of 5‐HT in cocaine action, we have developed a novel knock‐in (KI) mouse model wherein the Slc6a4 gene has been mutated to eliminate high‐affinity binding of cocaine to the 5‐HT transporter (SERT Met172). Using synaptosomes, we assessed the loss of high‐affinity recognition of cocaine and its analog RTI‐55 in the KI vs WT mice ex vivo. For these agents, we observed an 80‐ and 650‐fold reduction in potency for 5‐HT uptake inhibition, respectively. No change was seen for amphetamine and methylenedioxymethamphetamine (MDMA). We then measured the preferences of KI vs WT mice for cocaine in the 2‐bottle choice paradigm. KI mice exhibited a reduced preference in the first week of administration relative to WT animals. By week two, the KI mice demonstrated an exaggerated preference for cocaine vs WT littermates. These finding reveal a significant, time‐dependent, suppressive role of SERT antagonism in the drive of mice to continue to consume cocaine. Our studies are now being extended to other behavioral paradigms used to study cocaine action, as well as to an evaluation of molecular changes that derive selectively from SERT antagonism by cocaine. Grant Funding Source : Supported by NIMH award MH094527 and the Swiss National Science Foundation