Serotonin transporter promoter polymorphism and dopaminergic sensitivity in alcoholics.
The central serotonin (5-HT) system plays an important role in the rewarding and addictive properties of alcohol by a direct activation of the mesolimbic dopamine (DA) system. An insertion/deletion (L/S) promoter polymorphism (5-HTTLPR) of the 5-HT transporter (5-HHT) gene (SLC6A4) has been shown to influence transcriptional activity. It is predicted that reduced transynaptic 5-HT neurotransmission in alcoholics with the L/L genotype of 5-HTTLPR would result in a change in DA function compared to the S/S genotype. Thus the present study has tested whether dopaminergic sensitivity is influenced by the 5-HTTLPR genotype. Dopaminergic sensitivity, 5-HTTLPR genotype and smoking status were assessed in 121 alcoholics. Dopaminergic sensitivity as an indicator of the functional state of the dopaminergic system was measured by the amount of growth hormone (GH) secretion after subcutaneous administration of apomorphine (APO, 0.01 mg/kg). 5-HTTLPR genotype was significantly associated with dopaminergic sensitivity (P = 0.004) explaining 9.2% of the variance of GH response. Subjects homozygous for the L allele (with high 5-HTT expression) showed the lowest GH response, whereas those homozygous for the S allele (with low 5-HTT expression) showed the highest GH response (this was intermediate in heterozygous participants). Furthermore smoking was associated with a significantly reduced GH response (P = 0.006). Our findings indicate that the postsynaptic dopaminergic sensitivity is influenced by the 5-HTTLPR genotype. It is hypothesized that the reduction of sensitivity of the central DA receptors in alcoholics with the L/L genotype might be due to their higher vulnerability to the neurotoxic effects of chronic alcohol consumption than the S carriers.
Budde
Henning
H
Department of Movement and Training Science, Institute of Sport Science, Humboldt University, Philippstrasse 13, 10115, Berlin, Germany.
Sander
Thomas
T
Wernicke
Catrin
C
Müller
Anett
A
Gallinat
Jürgen
J
Schmidt
Lutz G
LG
Smolka
Michael N
MN
D000437:Alcoholism / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000704:Analysis of Variance; D001058:Apomorphine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D005838:Genotype; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012907:Smoking / Q000097:blood / Q000235:genetics / Q000378:metabolism
D018491:Dopamine Agonists; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D013006:Growth Hormone; D001058:Apomorphine; D004298:Dopamine