Acute and Long-Term Response of Dopamine Nigrostriatal Synapses to a Single, Low-Dose Episode of 3-Nitropropionic Acid-Mediated Chemical Hypoxia

The goal of the present investigation was to determine the persistence of striatal (DA) dopaminergic dysfunction after a mild chemically induced hypoxic event in Fisher 344 rats. To this end, we gave a single injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP; 16.5 mg/kg, i.p.) to 2-month old male F344 rats and measured various indices of striatal DA functioning and lipid peroxidation over a 3-month span. Separate groups of rats were used to measure rod walking, evoked DA release, DA content, malondialdehyde (MDA) accumulation, DA receptor binding, and tyrosine hydroxylase (TH) activity. The results showed that 3-NP exposure reduced most measures of DA functioning including motoric ability, DA release, and D-2 receptor densities for 1 to 3 months postdrug administration. Interestingly, DA content was reduced 1 week after 3-NP exposure, but rose to 147% of control values 1 month after 3-NP treatment. MDA accumulation, a measure of lipid peroxidation activity, was increased 24 h and 1 month after 3-NP treatment. 3-NP did not affect TH activity, suggesting that alterations in DA functioning were not the result of nigrostriatal terminal loss. These data demonstrate that a brief mild hypoxic episode caused by 3-NP exposure has long-term detrimental effects on the functioning of the nigrostriatal DA system. Synapse 65:339-350, 2011. (C) 2010 Wiley-Liss, Inc.