A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity.
BACKGROUND
Genetic variation of the promoter for the serotonin transporter (5-HTT) gene has been associated with its functional capacity. In vitro, carriers of a short allele (s-carriers) of the 5-HTT promoter display significant reduction in 5-HTT capacity. Dysfunction of 5-HTT has been observed in alcoholic individuals. We assessed whether the allelic constitution of the 5-HTT gene is associated with reduced serotonin transporter availability among alcoholic individuals.


METHODS
We genotyped the 5-HTT promoter region and measured the availability of serotonin transporter protein with [I-123]beta-CIT SPECT in the raphe area in 14 abstinent male alcoholic subjects and 8 age-matched control subjects of European American descent.


RESULTS
Among control subjects, the ratio of in vivo 5-HTT availability for ll-homozygous individuals relative to s-carriers was comparable to serotonin uptake ratios measured in vitro. There was a significant interaction of diagnosis and 5-HTT promoter genotype on 5-HTT availability (p <.01). Among controls, ll-homozygous individuals displayed a significant increase as compared with s-carriers. The availability of raphe 5-HTT was significantly reduced in ll-homozygous alcoholic individuals and was negatively correlated with their amount of alcohol consumption. Among s-carriers, 5-HTT availability did not differ significantly between control and alcoholic subjects.


CONCLUSIONS
Our preliminary findings suggest an association between 5-HTT allelic constitution and in vivo measurements of human serotonin transporter availability, and a potentially selective susceptibility of ll-homozygous individuals to the neurotoxic effects of chronic excessive alcohol consumption.
Heinz
A
A
Clinical Brain Disorders Branch, Intramural Research Program, NIMH, Bethesda, Maryland 20892-1379, USA.
Jones
D W
DW
Mazzanti
C
C
Goldman
D
D
Ragan
P
P
Hommer
D
D
Linnoila
M
M
Weinberger
D R
DR
D000328:Adult; D020268:Alcohol-Induced Disorders, Nervous System / Q000235:genetics / Q000378:metabolism*; D000437:Alcoholism / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism*; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D003042:Cocaine / Q000031:analogs & derivatives; D000431:Ethanol / Q000633:toxicity*; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013695:Temperance; D015899:Tomography, Emission-Computed, Single-Photon
D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D000431:Ethanol; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine