Fluoxetine-induced alterations in human platelet serotonin transporter expression: serotonin transporter polymorphism effects.
OBJECTIVE
Long-term antidepressant drug exposure may regulate its target molecule - the serotonin transporter (SERT). This effect could be related to an individual's genotype for an SERT promoter polymorphism (human serotonin transporter coding [5-HTTLPR]). We aimed to determine the effects of fluoxetine exposure on human platelet SERT levels.


METHODS
We harvested platelet samples from 21 healthy control subjects. The platelets were maintained alive ex vivo for 24 hours while being treated with 0.1 muM fluoxetine or vehicle. The effects on SERT immunoreactivity (IR) were then compared. Each individual's SERT promoter genotype was also determined to evaluate whether fluoxetine effects on SERT were related to genotype.


RESULTS
Fluoxetine exposure replicably altered SERT IR within individuals. Both the magnitude and the direction of effect were related to a person's SERT genotype. People who were homozygous for the short gene (SS) displayed decreased SERT IR, whereas those who were homozygous for the long gene (LL) demonstrated increased SERT IR. A mechanistic experiment suggested that some individuals with the LL genotype might experience increased conversion of complexed SERT to primary SERT during treatment.


CONCLUSIONS
These preliminary results suggest that antidepressant effects after longer-term use may include changes in SERT expression levels and that the type and degree of effect may be related to the 5-HTTLPR polymorphism.
Little
Karley Y
KY
Department of Psychiatry, University of Michigan and Ann Arbor VAMC, Ann Arbor, MI 48105, USA. kylittle@umich.edu
Zhang
Lian
L
Cook
Edwin
E
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D006580:Genetic Carrier Screening; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000187:drug effects* / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics*
D018687:Antidepressive Agents, Second-Generation; D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine