Short allele of 5-HTTLPR as a risk factor for the development of psychosis in Japanese methamphetamine abusers.
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.
Ezaki
Norikazu
N
Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Nakamura
Kazuhiko
K
Sekine
Yoshimoto
Y
Thanseem
Ismail
I
Anitha
Ayyappan
A
Iwata
Yasuhide
Y
Kawai
Masayoshi
M
Takebayashi
Kiyokazu
K
Suzuki
Katsuaki
K
Takei
Nori
N
Iyo
Masaomi
M
Inada
Toshiya
T
Iwata
Nakao
N
Harano
Mutsuo
M
Komiyama
Tokutaro
T
Yamada
Mitsuhiko
M
Sora
Ichiro
I
Ujike
Hiroshi
H
Mori
Norio
N
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
D000697:Central Nervous System Stimulants; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D008694:Methamphetamine