Abstract
Background: Heritable variation in brain monoaminergic activity has been suggested
to lead to interindividual differences in vulnerability to alcoholism, and many other
behavioral disorders. We evaluated if a functional Cys23Ser polymorphism in the 5–HT2C
receptor gene, the principal serotonin receptor in the brain, contributes to variation
in serotonin, norepinephrine and dopamine activity, as indexed by their major metabolite
concentrations in cerebrospinal fluid (CSF). Genotype–monoamine metabolite concentration
associations were subsequently correlated to risk for alcoholism.
Methods: The study sample consisted of unrelated Finnish males, including 214 alcoholic,
violent offenders and 222 population controls who were interviewed using the Structured
Clinical Interview for DSM-III-R, blind rated for psychiatric diagnoses and typed
for the HTR2C Cys23Ser polymorphism. CSF concentrations of 5-hydroxyindoleacetic acid
(5-HIAA), the major metabolite of serotonin, 3-methoxy-4-hydroxyphenylethyleneglycol
(MHPG), the major metabolite of norepinephrine, and homovanillic acid (HVA), the major
metabolite of dopamine were available from 195 individuals.
Results: The major finding in this study was that HTR2C CysSer23 significantly contributed
to CSF MHPG concentrations (p = .012). Higher concentrations of CSF MHPG were observed both in alcoholic violent
offenders and population controls with HTR2C Ser23 genotype. Despite the association
of Cys23Ser to CSF MHPG, HTR2C genotype was not associated with alcoholism, nor with
other psychiatric disorders present in this sample.
Conclusions: We conclude that a functional HTR2C Cys23Ser polymorphism contributes
to the interindividual genetic variation of CSF MHPG explaining 3% of the total variance.
This finding suggests that 5-HT2C receptors are involved in the regulation of norepinephrine
turnover in humans; however, HTR2C Cys23Ser does not appear to contribute to the risk
of alcoholism, or its contribution to this complex and heterogenous disorder is too
small to be detected by a sample of this size and structure.
Keywords
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Article info
Publication history
Accepted:
November 9,
1998
Received in revised form:
November 2,
1998
Received:
July 6,
1998
Identification
Copyright
© 1999 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
