Parkinson's disease (PD) is characterized by a selective loss of nigrostriatal dopamine neurons and dopamine innervation to the striatum. Results of epidemiological studies suggest that pesticide exposure is a risk factor for PD, and levels of organochlorine pesticides in post-mortem brain tissue have been shown to be associated with diagnosis of PD. The specific targeting of the SNc dopamine neurons in MPTP toxicity and idiopathic PD has been proposed to be mediated by the plasma membrane dopamine transporter (DAT), which acts as the molecular gateway for MPP+, the toxic metabolite of MPTP. Inside the cell, MPP+ can inhibit mitochondrial respiration and lead to free radical production, or be sequestered into vesicles by the vesicular monoamine transporter (VMAT2). The principal investigator has shown that in vivo exposure to organochlorine pesticides increases dopamine transport via an upregulation of DAT in mouse striatum. He hypothesizes that: 1) exposure to organochlorine pesticides such as heptachlor alters normal dopaminergic function, and 2) organochlorine pesticide-induced alterations to the nigrostriatal dopamine system increase susceptibility to dopaminergic toxins. Cell lines expressing both DAT and VMAT2, transgenic mice expressing different levels of DAT and/or VMAT2, and techniques to assess dopamine function will be used to test these ideas. There are five specific aims.
Aim 1 will determine the effects of organochlorine pesticides on plasma membrane and vesicular uptake of dopamine and on DAT and VMAT2 expression in stable cell lines.
Aim 2 will characterize mRNA and protein expression of DAT, VMAT2, TH, Dl and D2 receptors in the brain, focusing on the nigrostriatal system of heptachlor treated mice.
Aim 3 will determine whether heptachlor alters real time dopamine release and uptake using fast scan cyclic voltammetry in vitro, and whether heptachlor alters extracellular dopamine levels in vivo using microdialysis in freely moving animals.
Aim 4 will determine whether organochlorine pesticides augment the toxicity of PP+ in stable cell lines expressing DAT and/or VMAT2. Finally aim 5 will determine whether exposure to organochlorine pesticides increases the subsequent toxicity of MPTP in wild type and DAT-VMAT transgenic mice. The proposed experiments should advance our understanding of the effects of pesticides on dopamine signal transduction and ultimately the onset of PD and other disorders in which dopamine is involved. In addition, these studies could aid in the development of strategies aimed at attenuating the adverse effects of pesticides on the dopamine system.
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