Cerebral spinal fluid (CSF) 5-HIAA, the principal metabolite of serotonin, can identify individuals with a deficit of central nervous system serotonin metabolism. Decreased serotonin metabolism, as indicated by low CSF 5-HIAA, is postulated to be connected with behaviors including alcoholics characterized by deficient impulse control. Trait differences in CSF 5-HIAA concentration may be due to genetic variants of genes regulating serotonin metabolism. To identify factors controlling serotonin-dependent behaviors, we have focused our efforts on tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, and the 5-HT receptor which, in part, regulates serotonergic activity. The human TPH gene was mapped to chromosome 11p15.5, a human TPH variant in intron 7, associated with CSF 5-HIAA concentration in alcoholic, impulsive, Finnish offenders. The variant also associated with a history of suicidal attempts and of multiple suicidal attempts in alcoholic Finnish offenders. This finding of an association of the TPH variant with suicidal behavior has been replicated in a new population of Finnish alcoholic offenders. When we combine the two studies the association of TPH to suicide history is significant in both the impulsive group and the total alcoholic offender sample. Linkage of TPH has been found to alcoholism, history of suicide attempts and of medically-damaging suicide attempts and to KSP socialization score. The TPH variants have been sequenced and no alteration in mRNA splicing was observed. Three additional TPH variants have been identified and are being characterized. Three variants of the human 5-HT1A gene have been identified by single-strand conformational polymorphism (SSCP) analysis. Two variants change the protein sequence and the third is silent. The Ser22 variant in the extracellular amino- terminus of the human 5-HT1A receptor stably expressed in CHO-K1 cells decreases agonist-promoted down-regulation and desensitization of receptor expression. In addition, an allelic variant has been identified in the 5-HT1A gene in vervet monkeys. We are studying the relationship of the vervet variant to CSF 5-HIAA and prosocial behaviors.
