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The Journal of Neuroscience, September 17, 2008, 28(38):9585-9597; doi:10.1523/JNEUROSCI.5698-07.2008

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Neurobiology of Disease
Decreased Striatal Dopamine Release Underlies Increased Expression of Long-Term Synaptic Potentiation at Corticostriatal Synapses 24 h after 3-Nitropropionic-Acid-Induced Chemical Hypoxia

Garnik Akopian,¹ Cynthia Crawford,⁴ M. Flint Beal,⁵ Maurand Cappelletti,¹ Michael W. Jakowec,² Giselle M. Petzinger,² Ling Zheng,² Stacey L. Gheorghe,⁴ Carmela M. Reichel,⁴ Robert Chow,³ and John P. Walsh¹

¹Davis School of Gerontology, ²Department of Neurology, and ³Zilkha Neurogenetics Institute, University of Southern California, Los Angeles, California 90089, ⁴Department of Psychology, California State University, San Bernardino, California 92407, and ⁵Department of Neurology, Cornell University Medical College, New York, New York 10021

Correspondence should be addressed to Dr. John P. Walsh, Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089. Email: jwalsh{at}usc.edu

The striatum is particularly sensitive to the irreversible inhibitor of succinate dehydrogenase 3-nitropropionic acid (3-NP). In the present study, we examined early changes in behavior and dopamine and glutamate synaptic physiology created by a single systemic injection of 3-NP in Fischer 344 rats. Hindlimb dystonia was seen 2 h after 3-NP injections, and rats performed poorly on balance beam and rotarod motor tests 24 h later. Systemic 3-NP increased NMDA receptor-dependent long-term potentiation (LTP) at corticostriatal synapses over the same time period. The 3-NP-induced corticostriatal LTP was not attributable to increased NMDA receptor number or function, because 3-NP did not change MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine] binding or NMDA/AMPA receptor current ratios. The LTP seen 24 h after 3-NP was D₁ receptor dependent and reversed by exogenous addition of dopamine or a D₂ receptor agonist to brain slices. HPLC and fast-scan cyclic voltammetry revealed a decrease in dopamine content and release in rats injected 24 h earlier with 3-NP, and much like the enhanced LTP, dopamine changes were reversed by 48 h. Tyrosine hydroxylase expression was not changed, and there was no evidence of striatal cell loss at 24–48 h after 3-NP exposure. Sprague Dawley rats showed similar physiological responses to systemic 3-NP, albeit with reduced sensitivity. Thus, 3-NP causes significant changes in motor behavior marked by parallel changes in striatal dopamine release and corticostriatal synaptic plasticity.

Key words: LTP; LTD; voltammetry; NMDA; D₁; D₂

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Received July 9, 2007; revised Aug. 15, 2008; accepted Aug. 19, 2008.

Correspondence should be addressed to Dr. John P. Walsh, Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089. Email: jwalsh{at}usc.edu

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