Effect of Chronic Methylphenidate Treatment in a Female Experimental Model of Parkinsonism.

Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of ADHD in males and females. However, a majority of previous studies investigated the effect of MPH in only males, and little is known regarding consequences of female exposure to MPH. This is unfortunate because the few studies that have been conducted indicate that females have a greater sensitivity to MPH. Previous research in male mice has shown that chronic exposure to MPH causes dopaminergic neurons within the nigrostriatal pathway to be more sensitive to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, estrogen has been shown to protect dopaminergic neurons from MPTP neurotoxicity. Therefore, in this study, we test the hypothesis that chronic MPH exposure in female mice will render dopaminergic neurons in the nigrostriatal pathway more sensitive to MPTP, and that estrogen may play a protective role. Interestingly, proestrus females exhibited greater sensitivity to MPTP, with significantly reduced dopaminergic neurons in the SN and significant increases in DA quinone production. Chronic MPH exposure contributed to GSH depletion, but surprisingly, it did not increase dopamine quinone levels or dopaminergic cell loss. There were no significant differences in anestrus animals, with the exception of a depletion in GSH seen when animals received chronic high-dose (10 mg/kg) MPH followed by MPTP. Thus, estrogen may actually sensitize neurons to MPTP in this model, and chronic MPH may contribute to GSH depletion within the striatum. This study provides insight into how chronic psychostimulant use may affect males and females differently.

Chronic methylphenidate induces increased quinone production and subsequent depletion of the antioxidant glutathione in the striatum.

BACKGROUND: Methylphenidate (Ritalin®) is a psychostimulant used chronically to treat attention deficit hyperactivity disorder. Methylphenidate acts by preventing the reuptake of dopamine and norepinephrine, resulting in an increase in these neurotransmitters in the synaptic cleft. Excess dopamine can be autoxidized to a quinone that may lead to oxidative stress. The antioxidant, glutathione helps to protect the cell against quinones via conjugation reactions; however, depletion of glutathione may result from excess quinone formation. Chronic exposure to methylphenidate appears to sensitize dopaminergic neurons to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We hypothesized that oxidative stress caused by the autooxidation of the excess dopamine renders dopaminergic neurons within the nigrostriatal pathway to be more sensitive to MPTP. METHODS: To test this hypothesis, male mice received chronic low or high doses of MPH and were exposed to saline or MPTP following a 1-week washout. Quinone formation in the striatum was examined via dot blot, and striatal GSH was quantified using a glutathione assay. RESULTS: Indeed, quinone formation increased with increasing doses of methylphenidate. Additionally, methylphenidate dose-dependently resulted in a depletion of glutathione, which was further depleted following MPTP treatment. CONCLUSIONS: Thus, the increased sensitivity of dopamine neurons to MPTP toxicity following chronic methylphenidate exposure may be due to quinone production and subsequent depletion of glutathione.

Dopaminergic Effects of Major Bath Salt Constituents 3,4-Methylenedioxypyrovalerone (MDPV), Mephedrone, and Methylone Are Enhanced Following Co-exposure.

Designer drug mixtures popularized as "bath salts" often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in various combinations. However, most preclinical investigations have only assessed the effects of individual bath salt constituents, and little is known about whether co-exposure to MDPV, mephedrone, and methylone produces significant neuropharmacological interactions. This study evaluated and compared how MDPV, mephedrone, and methylone influence discrete brain tissue dopamine (DA) levels and motor stimulant responses in mice when administered alone and as a ternary mixture. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline or 1 or 10 mg/kg doses of MDPV, mephedrone, or methylone, or a cocktail of all three cathinones at doses of 1, 3.3, or 10 mg/kg each. The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure using HPLC-ECD. Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. MDPV, mephedrone, and methylone produced dose-related increases in mesolimbic and nigrostriatal DA levels that were significantly enhanced following their co-administration. In addition, mice treated with the cathinone cocktail displayed decreased locomotor activity on day 1 that was exacerbated by day 7 and not observed with any of the drugs alone. Our findings demonstrate a significant enhanced effect of MDPV, mephedrone, and methylone on both DA, and these effects on DA result in significant alterations in locomotor activity.

Neurogenesis within the hippocampus after chronic methylphenidate exposure.

Methylphenidate is a psychostimulant used to treat attention deficit hyperactivity disorder. Neurogenesis occurs throughout adulthood within the dentate gyrus of the hippocampus and can be altered by psychoactive medications; however, the impact of methylphenidate on neurogenesis is not fully understood. We investigated the effects of chronic low (1 mg/kg) and high (10 mg/kg) intraperitoneal doses of methylphenidate on neurogenesis in mouse hippocampus following 28 days and 56 days of treatment. Interestingly, methylphenidate, at both doses, increased neurogenesis. However, if methylphenidate treatment was not continued, the newly generated cells did not survive after 28 days. If treatment was continued, the newly generated neurons survived only in the mice receiving low-dose methylphenidate. To investigate the mechanism for this effect, we examined levels of proteins linked to cell proliferation in the hippocampus, including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB), and beta-catenin. BDNF or GDNF levels were not significantly different between groups. However, hippocampal VEGF, TrkB, and beta-catenin were significantly increased in mice receiving low-dose methylphenidate for 28 days compared to controls. Interestingly, high-dose methylphenidate significantly decreased beta-catenin after 28 days and decreased VEGF, beta-catenin, and TrkB after 56 days compared to controls. Thus, low-dose methylphenidate appears to increase cell proliferation and cell survival in the hippocampus, and these effects may be mediated by increase in VEGF, TrkB, and beta-catenin. While high dose methylphenidate may initially increase neuronal proliferation, newly generated neurons are unable to survive long-term, possibly due to decrease in VEGF, TrkB and beta-catenin.