title: Short allele of 5-HTTLPR as a risk factor for the development of psychosis in Japanese methamphetamine abusers.
abstract: Accumulating evidence suggests that genetic factors contribute to the vulnerability to methamphetamine (MAP) abuse and associated psychiatric symptoms. Chronic MAP abuse leads to psychosis, which may be of a transient or a prolonged type. Serotonergic dysfunction has been proposed as one of the contributory factors in the development of MAP psychosis. Our PET studies revealed that the serotonin transporter (5-HTT) density in global brain regions is significantly lower in MAP abusers. In this study, we examined the role of a functional polymorphism in the 5' flanking region of the 5-HTT gene (5-HTTLPR) in the development of MAP psychosis in a Japanese population. We analyzed DNA samples from 166 MAP patients (95 with transient and 71 with prolonged psychosis) and 197 age-, sex-, and geographic-origin-matched healthy controls. Patients were also subdivided according to the presence (n= 119) or absence (n= 148) of spontaneous relapse. We observed significant genotypic association of the 5-HTTLPR polymorphism with MAP psychosis (P= 0.022), particularly in patients who show prolonged psychosis. The frequency of the S allele in patients with prolonged psychosis was significantly higher than that of the controls (P= 0.045); it was further higher in patients with prolonged psychosis with spontaneous relapse (P= 0.004). 5-HTTLPR has been suggested to regulate the transcriptional activity of 5-HTT, with S alleles showing lesser transcriptional efficiency and also lower 5-HT(1A) receptor-binding potential. Prolonged MAP use, combined with the high frequency of 5-HTTLPR S-alleles, may lead to reduced 5-HTT levels and 5-HT(1A) receptor-binding potential in the brain, resulting in the dysfunction of the serotonergic system. Thus, we suggest a possible role for the 5-HTTLPR polymorphism in MAP psychosis.
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ezaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yoshimoto
authors.initials: Y
authors.lastname: Sekine
authors.forename: Ismail
authors.initials: I
authors.lastname: Thanseem
authors.forename: Ayyappan
authors.initials: A
authors.lastname: Anitha
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Iwata
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kawai
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Takebayashi
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Suzuki
authors.forename: Nori
authors.initials: N
authors.lastname: Takei
authors.forename: Masaomi
authors.initials: M
authors.lastname: Iyo
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Harano
authors.forename: Tokutaro
authors.initials: T
authors.lastname: Komiyama
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.forename: Norio
authors.initials: N
authors.lastname: Mori
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D055030:Drug Users; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011605:Psychoses, Substance-Induced / Q000235:genetics*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012307:Risk Factors; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D000697:Central Nervous System Stimulants; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D008694:Methamphetamine