Elsevier

Neuroscience

Volume 161, Issue 3, 7 July 2009, Pages 940-949
Neuroscience

Systems Neuroscience
Research Paper
In vivo dopamine release and uptake impairments in rats treated with 3-nitropropionic acid

https://doi.org/10.1016/j.neuroscience.2009.03.083Get rights and content

Abstract

Recent evidence has suggested that mitochondrial dysfunction may lead to impaired neurotransmitter exocytosis in transgenic Huntington's disease (HD) model mice. To gain insight into the impact of mitochondrial impairment on striatal dopamine release in vivo, we used fast-scan cyclic voltammetry (FSCV) at carbon fiber microelectrodes to measure dopamine release and uptake kinetics in anesthetized Lewis rats continuously treated for 5 days with 3-nitropropionic acid (3NP). Our results indicate that, even though striatal dopamine content was unchanged, remotely stimulated dopamine release evoked per electrical stimulus pulse ([DA]p) is decreased in 3NP-treated rats (33% of that observed in sham control rats) and that this decrease is uniform throughout all stereotaxic depths tested. Nevertheless, unlike data collected previously from transgenic HD model rodents, the maximum rate of dopamine uptake (Vmax) in 3NP-treated rats is diminished (30% of controls) while Km is unchanged. Treatment with 3NP also resulted in a corresponding decrease in locomotor activity, presumably due in part to the impaired dopamine release. These results indicate that dopamine release is degraded in this HD model, as is observed in transgenic HD model rodents; however, the results also imply that there are fundamental differences in dopamine uptake between 3NP-treated animals and transgenic animals.

Section snippets

Materials

3NP was obtained from Fluka (Sigma-Aldrich, St. Louis, MO, USA). Prior to administration to rats, 3NP was dissolved in water, adjusted to pH 7.3 with 5 M NaOH, and stabilized at pH 7.3-7.4 with 0.1 M phosphate-buffered saline.

Animals

Male Lewis rats (Charles River Laboratories, Inc., Wilmington, MA, USA), 12 weeks of age and weighing 300–350 g, were housed one per cage in plastic cages with food and water available ad libitum in a temperature/humidity-controlled environment on a 12-h light/dark cycle.

Striatal dopamine release is attenuated in 3NP-treated rats

We employed FSCV to measure the maximum amount of evoked dopamine release, [DA]max, in the striatum of rats that had been treated with 3NP for 5 days. Representative data are shown in Fig. 1. Immediately after the initiation of the series of 120 biphasic electrical stimulus pulses, dopamine release was detected by the carbon-fiber microelectrode in both sham rats and 3NP-treated rats. Cyclic voltammograms, placed above the stimulated release plots, confirm that the electroactive species is

Discussion

In this study, we examined the impact of systemic 3NP treatment on dopamine release and uptake in Lewis rats. Even though striatal dopamine content was unchanged, dopamine release ([DA]max) and the maximum rate of dopamine uptake (Vmax) were decreased in 3NP-treated rats compared to sham control rats. The Michaelis–Menten constant, Km, was unchanged by 3NP treatment. Dopamine release was impaired uniformly at multiple depths in the dorsal striatum and was not accompanied by the release of other

Conclusion

In summary, this work identifies deficiencies in dopamine release and uptake parameters, measured in vivo, in 3NP chemically-induced HD model rats. These deficiencies correlate with locomotor impairments. Studies aimed at understanding how changes in dopamine signaling contribute to behavior in HD have gained recent interest. Thus, given the extensive use of 3NP-treated HD model rats and the therapeutic potential of dopamine modulation in HD, it is important to clearly assess how dopamine

Acknowledgments

The authors acknowledge Prof. Emmanuel Brouillet, Unité de Researche Associée Commissariat à l'Energie Atomique, Orsay, France, for advice with the 3NP experimental protocol and Prof. R. Mark Wightman, University of North Carolina, Chapel Hill and Dr. Michael L. A. V. Heien, Penn State University, for TarHeel voltammetry software. The authors also acknowledge Prof. Stephen C. Fowler, University of Kansas, for advice on the behavioral experimentation. This research was supported by grants from

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