Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss.
Creator
Alam Gelareh; Edler Melissa; Burchfield Shelbie L; Richardson Jason R
Publisher
Neurotoxicology
Date
2017
2017-05
Description
Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical neurotoxicant used in mice to mimic primary features of PD pathology including striatal dopamine depletion and dopamine neuron loss in the substantia nigra pars compacta (SNc). In the literature, there are several experimental paradigms involving multiple doses of MPTP that are used to elicit dopamine neuron loss. However, a recent study reported that a single low dose caused significant loss of dopamine neurons. Here, we determined the effect of a single intraperitoneal injection of one of three doses of MPTP (0.1, 2 and 20mg/kg) on dopamine neurons, labeled by tyrosine hydroxylase (TH(+)), and total neuron number (Nissl(+)) in the SNc using unbiased stereological counting. Data reveal a significant loss of neurons in the SNc (TH(+) and Nissl(+)) only in the group treated with 20mg/kg MPTP. Groups treated with lower dose of MPTP (0.1 and 2mg/kg) only showed significant loss of TH(+) neurons rather than TH(+) and Nissl(+) neurons. Striatal dopamine levels were decreased in the groups treated with 2 and 20mg/kg MPTP and striatal terminal markers including, TH and the dopamine transporter (DAT), were only decreased in the groups treated with 20mg/kg MPTP. These data demonstrate that lower doses of MPTP likely result in loss of TH expression rather than actual dopamine neuron loss in the SN. This finding reinforces the need to measure both total neuron number along with TH(+) cells in determining dopamine neuron loss.
Methamphetamine-induced Loss Of Striatal Dopamine Innervation In Bdnf Heterozygote Mice Does Not Further Reduce D-3 Receptor Concentrations
Creator
Joyce J N; Renish L; Osredkar T; Walro J M; Kucera J; Dluzen D E
Publisher
Synapse
Date
2004
2004-04
Description
Depletion of dopamine (DA) reduces D, receptor number, but D-3 receptor expression is also regulated by brain-derived neurotrophic factor (BDNF). We took advantage of transgenic heterozygous BDNF mutant mice (+/-) to determine if reduced BDNF and loss of DA fibers produced by methamphetamine were additive in their impact on D-3 receptor number. We assessed selective markers of the dopaminergic system including caudate-putamen DA concentrations and quantitative autoradiographic measurement of tyrosine hydroxylase (TH) levels, DA transporter (DAT), and DA D-3 receptor binding between vehicle and methamphetamine-treated BDNF +/- and their wildtype (WT) littermate control mice. Caudate-putamen DA concentrations, TH and DAT levels were significantly reduced following methamphetamine treatment in both WT and BDNF +/- mice. The extent of methamphetamine-induced reduction in TH and DAT was greater for the WT than BDNF +/- mice and DAT levels were also decreased to a greater extent in nucleus accumbens of WT as compared to BDNF +/- mice. Lower D-3 receptor existed in caudate-putamen and nucleus accumbens in BDNF +/- mice and these differences were not affected by methamphetamine treatment. Taken together, these results not only substantiate the importance of BDNF in controlling D-3 receptor expression, but also indicate that a methamphetamine-induced depletion of DA fibers fails to produce an additive effect with lowered BDNF for control of D-3 receptor expression. In addition, the reduction of D-3 receptor expression is associated with a decreased neurotoxic response to methamphetamine in BDNF +/- mice. (C) 2004 Wiley-Liss, Inc.