Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice

Background: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a ‘‘cognitive enhancer’ ’ and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings: Through the use of stereological counting methods, we observed a significant reduction (,20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChipH HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigr

Long-term organic carbon turnover rates in natural and semi-natural topsoils

We combined published and new radiocarbon and ancillary data for uncultivated topsoils (typically 15 cm depth), to make two databases, one for the United Kingdom (133 sites), and one global (114 sites). Forest topsoils are significantly higher in radiocarbon than non-forest soils, indicating greater enrichment with ‘‘bomb carbon’’ and therefore faster C turnover, if steady-state conditions are assumed. Steady-state modelling, taking into account variations in atmospheric 14CO2, including the effects of 20th century nuclear weapons testing and radioactive decay, was used to quantify soil carbon turnover rates. Application of a model with variable slow (20 year mean residence time, MRT) and passive (1,000 year MRT) carbon pools partitioned the topsoil C approximately equally, on average, between the two pools when the entire data set was considered. However, the mean slow:passive ratio of 0.65:0.35 for forest soil was highly significantly different (p\0.001) from the 0.40:0.60 ratio for non-forest soils. Values of the slow and passive fractions were normally distributed, but the non-forest fractions showed greater variation, with approximately twice the relative standard deviations of the forest values. Assuming a litter input of 500 g C m-2 a-1, average global C fluxes (g C m-2 a-1) of forest soils are estimated to be 298 (through a fast pool ofMRT1 year), 200 (slow pool) and 2.0 (passive pool), while for non-forest soils, respective average fluxes of 347, 150 and 3.3 g C m-2 a-1 are obtained. The results highlight the widespread global phenomenon of topsoil C heterogeneity, and indicate key differences between forest and non-forest soils relevant for understanding and managing soil C