Decreased striatal dopamine release underlies increased expression of long-term synaptic potentiation at corticostriatal synapses 24 h after 3-nitropropionic-acid-induced chemical hypoxia.

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 D(1) receptor dependent and reversed by exogenous addition of dopamine or a D(2) 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.