Serotonin Transporter and Seasonal Variation in Blood Serotonin in Families with Obsessive-Compulsive Disorder

Abstract

The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (1) and short (s) variants of theThe serotonin transporter (HTT = SLC6A4) is a plausible candidate gene for obsessive-compulsive disorder (OCD) and several other psychiatric disorders (Altemus et al. 1996;Lesch et al. 1995;Ogilvie et al. 1996). It has been associated with anxiety-related traits in two predominantly male samples (Gelernter et al. 1995;Ramamoorthy et al. 1993). A complementary deoxyribose nucleic acid (cDNA) encoding the 5-HTT in the human midbrain raphe complex has been isolated, and its identity with the human platelet serotonin (5-HT) transporter site has been demonstrated (Lesch et al. 1993a,b).HTT gene transcription is regulated by a deletion/ insertion polymorphism in the promoter (Heils et al. 1995). The long (I) and short (s) variants of this polymorphic region have different transcriptional efficiencies in transfection assays and lymphoblastoid cell lines Lesch et al. 1996). The short allele reduces the transcriptional efficiency of the HTT gene promoter, resulting in decreased 5-HTT binding and 5-HT uptake in lymphoblasts . Studies of HIT gene expression in lymphoblast cell lines from 10 subjects with different genotypes suggested that the polymorphism has more of a dominant-recessive than a codominant-additive effect, with the short variant ap-0893-133X/98/$19.00 PII S0893-133X(97)00097-3 NEUROPSYCHOPHARMACOLOGY 1998-VOL. 18, NO. 2 pearing dominant to the long variant. However, the dominant mode of action of the short allele has been questioned (Goldman 1996).Because of the small sample size in that study and the importance of the HTT, we examined the relationship between the HTT promoter variant and whole blood 5-HT concentration in 70 individuals from 20 families ascertained through children and adolescents between 10 and 17 years of age with a DSM-III-R diagnosis of OCD. Sampling through early-onset cases can be a useful strategy in identifying a more clearly genetic or homogeneous form of a disorder (Lander and Schork 1994). Family studies have demonstrated that OCD is often familial and that the morbid risk of the disorder is higher among the relatives of early-onset probands than among the relatives of late-onset probands (Bellodi et al. 1992;Pauls et al. 1995).The selective response of OCD to potent 5-HT transporter inhibitors (serotonin reuptake inhibitors, SRis) has suggested that a serotonergic abnormality may be involved in OCD (Goodman et al. 1990;Leonard et al. 1989). The 5-HTT is an initial site of action for those drugs and is crucial to the termination of serotonergic neurotransmission (Amara and Kuhar 1993). Two treatment studies of childhood OCD using clomipramine, a potent 5-HT transporter inhibitor, have demonstrated a significant correlation between clinical improvement and a marked reduction in either platelet 5-HT or whole blood 5-HT content, reflecting the effect of the drug on the platelet uptake site (F...

Early experience and serotonin transporter gene variation interact to influence primate CNS function

“…21 These results, along with some of the findings from previous human studies, [22][23][24] demonstrate a relationship between the 5-HTTLPR and 5-HT functioning in both human and nonhuman primates (but also see Naylor et al 25 and Jonsson et al 26 ). Although the 5-HTTLPR alleles are differentially active in vitro, relatively few studies have examined direct measures of CNS serotonin function in either humans or other animals.…”

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

“…Therefore, we also characterized hormonal responses in subjects expressing either the long or short form of a functional polymorphism within the serotonin transporter gene. In vitro and in vivo studies have shown that tissue expressing the long form of the polymorphism expresses more transporter mRNA and exhibits 2-fold greater serotonin uptake compared to cells expressing the short form of the allele (Hanna et al 1998;Lesch et al 1997;Little et al 1998). Because the short allele is associated with reduced transporter activity (greater synaptic serotonin concentration), it is possible that persons expressing the shorter allele would have greater serotonergic activity and thereby greater HPA axis activation compared to persons expressing only the long form of the allele.…”

“…The serotonin transporter regulates the concentration of serotonin within the synaptic cleft and thereby modulates magnitude and duration of serotonin-induced postsynaptic mediated signals (Lesch and Mossner 1998). Recently a functional polymorphism has been described in the promoter region of the transporter, which modulates transcriptional activity of this gene as well as tissue expression of transporter activity (Hanna et al 1998;Heils et al 1997;Little et al 1998). Like the A118G polymorphism in the mu-opioid receptor, it is plausible that this functional polymorphism within the serotonin transporter is associated with altered HPA axis dynamics.…”

Serotonin Transporter: A Potential Substrate in the Biology of Suicide

“…Additionally, the uptake of 5-HT is approximately two-fold higher in cells containing the homozygous ll form of the 5-HTTLPR than either the ls or ss forms (Lesch and Mossner, 1998). Other factors, such as seasonal variation, also interact with the 5-HTTLPR genotype to influence both the uptake potential and expression of the SERT (Hanna et al, 1998). Despite the influence of genotype on SERT expression and uptake, genotype has not been demonstrated to have any effect on 5-HT binding affinity (Greenberg, 1999).…”