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Methamphetamine (MAP) is one of the most commonly abused drugs in Asia, and previous studies suggest that serotonin 3 receptors (5-HT3) are involved in MAP-induced locomotion and reward. However, little is known about the role of 5-HT3 receptors in MAP-induced behavioral sensitization. Here, we measured the effects of MDL 72222, a 5-HT3 antagonist, and SR 57227 A, a 5-HT3 agonist, on the development and expression of MAP-induced behavioral sensitization, and alternations of 5-HT3 receptor binding labeled with the 5-HT3-selective antagonist, [3H]GR65630, in mice. In addition, we investigated the effects of MAP on 5-HT3A receptor channel activity in Xenopus laevis oocytes expressing 5-HT3A receptors. We found that MDL 72222 attenuated both the development and expression of behavioral sensitization to MAP (1.0 mg/kg, i.p.), and that this attenuating effect of MDL 72222 was reversed by pre-treatment with SR 57227 A. In oocytes expressing 5-HT3A receptor, MAP exhibited a dual modulation of 5-HT3A receptor channel activity, i.e. pre-treatment with a low dose of MAP (0.1 µm) enhanced 5-HT-induced inward peak current ( I5-HT) but a high dose of MAP (100 µm) inhibited I5-HT. The acute administration of MDL 72222 with MAP decreased [3H]GR65630 binding versus MAP alone in the mouse striatum. Our results suggest that MDL 72222 attenuates MAP-induced behavioral sensitization via 5-HT3 receptors in the caudate putamen, and that 5-HT3 receptor antagonists like MDL 72222 have potential as novel anti-psychotic agents for the treatment of MAP dependence and psychosis. [ABSTRACT FROM AUTHOR]

Chromosome translocations in peripheral blood lymphocytes of normal, healthy humans increase with age, but the effects of gender, race, and cigarette smoking on background translocation yields have not been examined systematically. Further, the shape of the relationship between age and translocation frequency (TF) has not been definitively determined. We collected existing data from 16 laboratories in North America, Europe, and Asia on TFs measured in peripheral blood lymphocytes by fluorescence in situ hybridization whole chromosome painting among 1933 individuals. In Poisson regression models, age, ranging from newborns (cord blood) to 85 years, was strongly associated with TF and this relationship showed significant upward curvature at older ages versus a linear relationship (p<0.001). Ever smokers had significantly higher TFs than non-smokers (rate ratio (RR)=1.19, 95% confidence interval (CI), 1.09-1.30) and smoking modified the effect of age on TFs with a steeper age-related increase among ever smokers compared to non-smokers (p<0.001). TFs did not differ by gender. Interpreting an independent effect of race was difficult owing to laboratory variation. Our study is three times larger than any pooled effort to date, confirming a suspected curvilinear relationship of TF with age. The significant effect of cigarette smoking has not been observed with previous pooled studies of TF in humans. Our data provide stable estimates of background TF by age, gender, race, and smoking status and suggest an acceleration of chromosome damage above age 60 and among those with a history of smoking cigarettes.