A new polymorphic 40-nucleotide repeat in the human dopamine transporter gene is described. It may underlie individual differences in susceptibility to several neuropsychiatric diseases.

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Human dopamine transporter gene (DAT1) has a variable number of tandem repeats (VNTR) in its 3Ј-untranslated region (UTR).The association between the VNTR polymorphism and neuropsychiatric disorders has been studied, but their relationship is still unclear. Here we identified a novel polymorphism in the 3Ј-UTR of the DAT1 gene, G2319A, and a significant association between the polymorphism and alcoholism was observed in both genotypic and allelic frequencies (P = 0.040 and 0.019, extended Fisher's exact test, respectively). There was a significant gene dose effect on the risk for alcoholism associated with the 2319-A allele ( 2 = 6.16, df = 2, P = 0.046, linearity tendency test: Cochranq-Armitage analysis). Moreover, in the haplotype analysis with G2319A-and VNTR-polymorphisms, a positive gene dose efffect on the risk with the A10 allele (P = 0.044, linearity tendency test) and a negative gene dose effect with the G10 allele (P = 0.010, linearity tendency test) for alcoholism were significantly detected. Odds ratio for alcoholism with the A10 and G10 alleles were 1.76 (1.12-2.76) and 0.53 (0.32-0.79), respectively. These results indicate that the DAT1 gene may confer vulnerability to alcoholism.

Prosaposin, a 51 7-amino-acid glycoprotein, not only acts as the precursor ofsaposin A, B, C, and 0 but also possesses neurotrophic activity to rescue hippocampal CAl neurons from ischemic damage in vivo and to promote neurite extension of neuroblastoma cells in vitro. Recently, the trophic activity of prosaposin on human neuroblastoma cells has been shown to reside in the NH 2-terminal hydrophilic sequence (LIDNNRTEEILY) of the human saposin C. Here we show that prosaposin, saposin C, and a peptide comprising the 18-amino-acid sequence (1 8-mer peptide; LSELIINNATEELLIKGL) located in the NH2-terminal hydrophilic sequence of the rat saposin C-domain promoted survival and neurite outgrowth of cultured rat hippocampal neurons in a dose-dependent manner. Moreover, infusion for 7 days of the 18mer peptide into the lateral ventricle of gerbils, starting either 2 h before or immediately after 3 mm of forebrain ischemia, protected ischemia-induced learning disability and hippocampal CAl neuronal loss. Thus, we ascribe the in vitro and in vivo trophic actions of prosaposin on hippocampal neurons to the linear 1 8-mer sequence and raise the possibility that this peptide can be used as an agent for the treatment of forebrain ischemic damage.Neurons were prepared separately from the rat hippocampi of 17-day embryos (Hatanaka et al., 1988) and cultured on plastic coverslips according to the procedures of Akaike et al. (1991) with slight modifications. In brief, the hippocampi were treated with trypsin and digested with DNase I (Sigma).

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