Overexpression of tyrosine hydroxylase in dopaminergic neurons increased sensitivity to methamphetamine.

Drug abuse is one of the great social problems in the world and a major healthcare challenge. It is supposed that sensitivity and reactivity to abuse drugs may vary from person to person, while its molecular basis is largely unknown. Dopaminergic neurons are deeply involved in addiction, and tyrosine hydroxylase (TH) catalyzes the first and rate-limiting step of the biosynthesis of dopamine (DA). We investigated the effects of increased TH expression on the metabolism of DA and reactivity to methamphetamine (METH), a drug of abuse, in mice. Wild-type TH (WT-TH) or the S40E mutant of TH (S40E-TH), which is an active form of TH mimicking phosphorylated TH at the 40th serine, was expressed in midbrain dopaminergic neurons using an adeno-associated virus (AAV) vector. The biochemical analysis showed that the turnover rates of DA in the nerve terminals were increased by the expression of WT-TH and S40E-TH, while there were few changes in the DA contents. Next, we administered METH to TH-overexpressing mice. We found that the S40E-TH-expressing mice responded to lower doses of METH than the control mice and WT-TH mice. The stereotyped behaviors appeared first in S40E-TH mice and then in WT-TH and control mice in this order. These data showed that the TH activity and expression level differentially affect DA metabolism in the nerve terminals from that in the cell bodies and that the TH activity and expression level are one of the determining factors for sensitivity and reactivity to METH. We suggest that TH may be a drug target for ameliorating sensitivity to drugs of abuse.

Aging increases oxidative stress in semen.

PURPOSE: As age increases, oxidative stress increases, sperm motility decreases, and DNA fragmentation increases. To date, reports of age-related effects on semen have focused on reactive oxygen species (ROS) or total antioxidant capacity (TAC) as indicators of oxidative stress. However, assessments of ROS and TAC must be considered within a more comprehensive context in order to correctly evaluate oxidative stress and interpret findings. In this regard, the purpose of this study was to investigate the relationship between the static oxidation reduction potential (sORP) and paternal age with the goal of using the sORP as an indicator of semen oxidative stress. MATERIALS AND METHODS: Semen samples from 173 men were analyzed for the following parameters: volume, motility, and beat cross frequency (BCF). The sORP was measured by using the MiOXSYS™ system. The correlation between semen parameters and the sORP level was analyzed as a function of age. The rate of sORP positivity was compared between men <34 and ≥34 years of age, with a positive sORP defined as a level ≥1.38. RESULTS: Volume, motility, and BCF were negatively correlated with age (p<0.001). The semen sORP level was positively correlated with age (p<0.05). The rate of sORP positivity was significantly increased in men ≥34 years of age compared with that in men <34 years of age (33% compared with 12%, respectively; p<0.01). CONCLUSIONS: The sORP may play a role in age-related decreases in semen parameters (volume, motility, and BCF). The rate of sORP positivity increased significantly after 34 years of age.