A rat model of hemidystonia induced by 3-nitropropionic acid.

Abstract

OBJECTIVE: Secondary dystonia commonly presents as hemidystonia and is often refractory to current treatments. We aimed to establish an inducible rat model of hemidystonia utilizing 3-nitropropionic acid (3-NP) and to determine the pathophysiology of this model. METHODS: Two different doses of 3-NP were stereotactically administered into the ipsilateral caudate putamen (CPu) of Wistar rats. Behavioral changes and alterations in the neurotransmitter levels in the basal ganglia were analyzed. We also performed an electromyogram, 7.0-T magnetic resonance imaging and transmission electron microscopy examination to determine the pathophysiology of the model. RESULTS: In the CPu region, 3-NP produced mitochondrial cristae rupture, axonal degeneration, increased excitatory synaptic vesicles and necrosis. The extracellular concentrations of excitatory amino acids increased, whereas the inhibitory amino acids decreased in the CPu. Furthermore, an imbalance of neurotransmitters was found in other regions of the basal ganglia with the exception of the external globus pallidus. This study demonstrated that 3-NP administration results in CPu damage, and combined with a neurotransmitter imbalance in the basal ganglia, it produces specific neurobehavioral changes in rats. Right limb (contralateral side of CPu lesion) and trunk dystonic postures, shortened step length and ipsiversive dystonic posturing were observed in these rats. Furthermore, EMG recordings confirmed that co-contraction of the agonist and antagonist muscles could be seen for several seconds in right limbs. CONCLUSIONS: Stereotactic injection of 3-NP into the ipsilateral CPu of rats established an inducible model for hemidystonia. This effect might result from an imbalance of neurotransmitter levels, which induce dysfunctional activity of the basal ganglia mainly via the cortico-striato-GPi direct pathway. Symptoms in this model were present for 1 week. Activation of the cortico-striato-GPe indirect pathway and rebalance of neurotransmitters may lead to recovery. This rat model may be a suitable tool used to understand and further investigate the pathophysiology of dystonia.