Inter-relationships of intermediate phenotypes for serotonin function, impulsivity, and a 5-HT2A candidate allele: His452Tyr.

Central serotonin (5-hydroxytryptamine, 5-HT) function has a role in a range of genetically influenced psychiatric diagnoses and behaviors. Several human 5-HT receptor polymorphisms are 'candidate alleles', altering in vitro function, and potentially affecting behavior and drug response. The 5-HT(2A) His452Tyr polymorphism alters signal transduction, and has been associated with diminished efficacy of clozapine in schizophrenia. Another 5-HT(2A) receptor polymorphism consists of the silent thymidine-cytosine substitution (102T>C), which has been controversially associated with schizophrenia. We investigated the role of His452Tyr and the 102T>C in behavior and in vivo intermediate biochemical phenotypes. Intracellular 5-HT-induced Ca(2+) release by platelets and fenfluramine-induced prolactin release by pituitary were evaluated in 27 psychiatrically interviewed subjects (including both impulsive patients and controls) stratified by His452Tyr genotype and also genotyped for a second 5-HT(2A) polymorphism, 102T>C. Subjects with increased measures of impulsivity showed decreased postreceptor 5-HT function, as indicated by reduced 5-HT-induced Ca(2+) release, but no alteration in net 5-HT function, as measured by fenfluramine response. No significant effects of either polymorphism were associated with altered 5-HT-induced calcium response or fenfluramine-stimulated prolactin release. One available Tyr452/Tyr452 homozygote had diminished Ca(2+) release and one of the highest levels of fenfluramine response. Although not statistically significant, the effect of the T102C, but not the His452Tyr, genotype on prolactin level change over time was associated with a medium to large strength of association (treatment magnitude of T(2)=0.10), suggesting that further study is warranted.