Ablation of the subthalamic nucleus supports the survival of nigral dopaminergic neurons after nigrostriatal lesions induced by the mitochondrial toxin 3‐nitropropionic acid

Abstract

We investigated the role of the excitatory afferents from the subthalamic nucleus (STN) in the death of nigral dopamine (DA) neurons after nigrostriatal axon terminal lesions. Nigral DA neurons were detected by use of both tyrosine hydroxylase immunolabeling or retrograde labeling of nigral cells with fluorogold. Sprague–Dawley rats were subjected to unilateral, quinolinic acid–induced destruction of the STN. Sham lesions of the STN were made by injecting phosphate-buffered saline. Two weeks after STN ablation, lesions of nigrostriatal DA neurons were induced by intrastriatal injections of either the mitochondrial toxin 3-nitropropionic acid (3-NP) or the catecholamine toxin 6-hydroxydopamine (6-OHDA). Intrastriatal injections of 3-NP or 6-OHDA caused a progressive loss of nigral tyrosine hydroxylase–positive or fluorogold-labeled DA neurons in a dose-dependent manner. Previous ablation of the STN significantly attenuates the loss of DA neurons in rats receiving 3-NP but not 6-OHDA. Sham lesions of the STN did not affect DA neuron death induced by the toxins. The results indicate that the excitatory inputs from the STN may contribute to the death of nigral DA neurons under a condition of 3-NP–induced metabolic impairment. Ann Neurol 1999;45:640–651