Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress.
BACKGROUND
Decreased sensitivity to alcohol has been demonstrated to be a predictor of alcoholism in humans, and variation in the gene-linked polymorphic region of the serotonin transporter (5-HTTLPR) is associated with the response to the motor-impairing effects of alcohol. In a nonhuman primate model of excessive alcohol intake, we have shown that decreased serotonin turnover is associated with both lower initial sensitivity to alcohol and higher prospective alcohol consumption using rhesus macaques. In addition, we have demonstrated that macaques separated from their mothers and reared in peer-only groups are more likely to consume alcohol as adults.


METHODS
To examine the relationship between serotonin transporter genotype, early rearing experience, and initial sensitivity to alcohol, peer- and mother-reared, adolescent, alcohol-naive rhesus macaques (n = 123) were rated for intoxication after intravenous administration of ethanol (2.2 g/kg and 2.0 g/kg for males and females, respectively) during two testing periods. Serotonin transporter (rh5-HTTLPR) genotype was determined using polymerase chain reaction followed by gel electrophoresis, and data were analyzed using ANOVA and the Mann-Whitney U test.


RESULTS
Our analyses demonstrate an effect of serotonin transporter gene variation on ethanol sensitivity, such that animals homozygous for the l allele exhibited decreased sensitivity to the ataxic and sedating effects of alcohol. This effect remained after correction for blood ethanol concentrations and birth cohort. When animals were segregated according to rearing condition, serotonin transporter gene variation predicted intoxication scores among peer-reared animals.


CONCLUSIONS
As in some human reports, this study demonstrates a diminution in the response to alcohol in animals homozygous for the l rh5-HTTLPR allele. The phenotypic expression of this genotype in l/s animals, however, is environmentally dependent.
Barr
Christina S
CS
Labortatory of Clinical Studies, Primate Unit, National Institute on Alcohol Abuse and Alcoholism, NIH Animal Center, PO Box 529, Building 112, Poolesville, MD 20837, USA. cbarr@mail.nih.gov
Newman
Timothy K
TK
Becker
Michelle L
ML
Champoux
Maribeth
M
Lesch
Klaus Peter
KP
Suomi
Stephen J
SJ
Goldman
David
D
Higley
J Dee
JD
D000435:Alcoholic Intoxication / Q000235:genetics*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D013312:Stress, Physiological
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D000431:Ethanol