Impact of genetic variability in the serotonin transporter, Tryptophan Hydroxylase-2, and Serotonin 2A Receptors on MDMA Use and Impulsivity

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Title: Impact of genetic variability in the serotonin transporter, Tryptophan Hydroxylase-2, and Serotonin 2A Receptors on MDMA Use and Impulsivity
Author: Nidal J. Moukaddam
Abstract: Ecstasy [MDMA ; ) -3 ,4 -methylenedioxymethamphetamine] is popular for positive effects including enhanced mood and empathy , despite potential deleterious physical and psychological consequences . The serotonin (5 -HT ) system plays a prominent role in the neurochemical and behavioral effects of MDMA , and preferentially targets 5 -HT neurons in humans , although this substituted amphetamine does have significant actions on other monoamine systems . Some negative effects of MDMA use , including mood and cognitive dysfunction , may involve the 5 -HT system , and are often treated with 5 -HTergic antidepressants . The involvement of specific 5 -HT genes , including tryptophan hydroxylase -2 (TPH -2 ) , 5 -HT transporter (5 -HTT ) , and 5 -HT2A receptor (5 -HT2AR ) in the effects of MDMA is incompletely understood . Our initial study compared the prevalence of polymorphisms leading to reduced gene expression in those genes among MDMA users versus controls , and assessed the relationship between these polymorphisms and impulsivity . As compared to control groups , MDMA users were less likely to carry 5 -HTT SS or 5 -HT2AR A1438G GG /T102C CC genotypes thought to lead to decreased gene expression . No relationship was found between genotype and impulsivity , however drug -naïve controls had lower impulsivity levels than either MDMA or polydrug users . The differential distribution of 5 -HTT and 5 -HT2AR 1438G / T102C suggests that these genes contribute to individuals’ choices of MDMA versus other drugs . The second study examined the relationship between TPH -2 , 5 -HTT , and 5 -HT2AR polymorphisms , and self -reported MDMA intake or impulsivity in moderate -to -heavy MDMA users . Decreased MDMA use was reported by individuals carrying genotypes associated with reduced gene expression (TPH -2 TT , 5 -HTT SS , 5 -HT2AR A1438G GG /T102C CC ) , and 5 -HTT genotype -dependent changes in impulsivity were found . Our studies are the first to show a differential allelic distribution between MDMA users and controls , and demonstrate the relationship between TPH -2 , 5 -HTT and 5 -HT2AR A1438G /T102C polymorphisms and MDMA intake . Individuals carrying TPH -2 TT , 5 -HTT SS , 5 -HT2AR A1438G GG /T102C CC may represent a subset of MDMA users at higher risk to develop MDMA -related adverse events , including depression . Further , this group may display poorer response to antidepressants and decreased retention in treatment given elevated impulsivity levels . Thus , our findings may have important implications for diagnosis and treatment of MDMA -dependent individuals .
URI: http : / /hdl .handle .net /2152 .3 /200
Date: 2008-08-19

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Impact of genetic variability in the serotonin transporter, Tryptophan Hydroxylase-2, and Serotonin 2A Receptors on MDMA Use and Impulsivity. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /200 .

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