Study of association between alpha-synuclein gene polymorphism and methamphetamine psychosis/dependence.

Methamphetamine (MAP) dissipates proton gradients across the membranes of synaptic vesicles, enhances cytoplasmic dopamine (DA) concentrations, and causes calcium-independent, nonvesicular DA release into synapses. MAP is taken into the cytosol by the dopamine transporter (DAT) on the synaptic terminals of DA neurons, and endogenous DA is concurrently released through the transporter by carrier exchange mechanisms, resulting in a robust increase in DA concentration in the synaptic clefts. The enhanced DA release through DAT by MAP is the main mechanism for the reinforcing effects of MAP. The complexes of alpha-synuclein and DAT facilitate membrane clustering of the DAT, thereby accelerating DA uptake in vitro. alpha-Synuclein has been shown to be overexpressed in the midbrain DA neurons of chronic cocaine abusers. The present study was performed to study the association between the alpha-synuclein gene polymorphisms and MAP psychosis/dependence in Japanese population. Since the T10A7 polymorphic site at the 5' end of the noncoding exon 1' in the alpha-synuclein gene is highly polymorphic, we analyzed the noncoding exon 1' and intron 1, including this polymorphic site by sequencing. We confirmed four single nucleotide polymorphisms (SNPs) within 1.38 kbp of the T10A7 polymorphic site. No significant difference was found in genotype or allele frequencies in the T10A7 polymorphic site between MAP psychotic/dependent and control subjects. We found significant association between three SNPs in the vicinity of this polymorphic site in intron 1 and MAP psychosis/dependence in female subjects, but not in males. These results suggest an association of the alpha-synuclein gene polymorphisms with MAP psychosis/dependence in our female subjects. Further analyses are necessary to clarify the gender difference, by using a larger sample size and/or different ethnic groups, as well as functional variations in the alpha-synuclein gene.