Subthalamic Ablation Reverses Changes in Basal Ganglia Oxidative Metabolism and Motor Response to Apomorphine Induced by Nigrostriatal Lesion in Rats

Abstract

In Parkinson's disease, the functional architecture of the basal ganglia nuclei undergoes profound alterations, one of the most important of which is overactivity of the basal ganglia output nuclei. This phenomenon seems to be intimately related to pathological overactivity of the subthalamic nucleus, which directly modulates the basal ganglia output through its glutamatergic projections. In this study, we investigated the effects of unilateral subthalamic nucleus lesions on the activities of succinate dehydrogenase and cytochrome oxidase, two markers of neuronal activity, in rats with prior unilateral lesions of the nigrostriatal tract. We also explored the effect of subthalamic nucleus lesions on the rotational response to systemic apomorphine. Rats with unilateral lesions of the nigrostriatal tract showed ipsilateral increases in enzyme activity in the basal ganglia output nuclei, entopeduncular nucleus and substantia nigra pars reticulata. Selective subthalamic nucleus destruction completely reversed this phenomenon. In addition, subthalamic nucleus lesions abolished the rotational response to apomorphine. These results confirm that overactivity of the subthalamic nucleus plays a pivotal role in the functional alterations of basal ganglia associated with Parkinson's disease. They also shed further light on the neural mechanisms through which manipulations of subthalamic activity can ameliorate Parkinson's disease symptoms.

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

“…Our results show that STN lesion performed 15 days after 6-OHDA lesion of the nigrostriatal pathway reduced the apomorphine-induced rotational behavior. These data agree with previous reports that STN lesion reduces the number of apomorphine-induced contralateral rotations (4,12,15). However, we found no improvement of hypokinesia in the open-field test.…”

“…Repeated stimulation with a DA agonist may produce an increase in DA-mediated behavioral responses (priming effect). Nevertheless, a two-week interval is probably enough time to avoid the priming effect of the first rotational test (12).…”

“…In experimental models of PD induced by parkinsonian neurotoxins such as 6-hydroxydopamine (6-OHDA) or 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP), inhibition of STN function by ablation (12)(13)(14)(15), HFS (16,17) or pharmacological antagonism (18,19) has been reported to ameliorate some of the parkinsonian motor deficits and even to protect nigrostriatal dopaminergic neurons against the injury induced by these neurotoxins. On the other hand, some investigators were unable to find any neuroprotective effects of STN inactivation on SNpc neuron survival (20)(21)(22).…”

The Response of Subthalamic Nucleus Neurons to Dopamine Receptor Stimulation in a Rodent Model of Parkinson’s Disease

“…The enhanced activity of these output structures in the dopamine-depleted state may be due, in part, to an elevation of the excitatory drive from the subthalamic nucleus (STN) (Miller and DeL ong, 1987). In accordance with this hypothesis, procedures thought to reduce subthalamic neuronal output have been found to reverse the behavioral effects of dopamine depletion in rats (Anderson et al, 1992;Blandini et al, 1995;Delfs et al, 1995), primates (Bergman et al, 1990;Aziz et al, 1991;Benazzouz et al, 1993), and humans (Benabid et al, 1994;Limousin et al, 1995;Pollak et al, 1996).…”

Group I mGluRs modulate calcium currents in rat GP: Functional implications

“…In our opinion, the functional impact of mGluRs on mammalian GP should become prominent, particularly in conditions of exorbitant release of endogenous glutamate from STN, such as parkinsonism. That the overexcitability of the STN (impinging on the medial and lateral pallidus, among others) plays a central role in the development of hypokinetic symptoms was recently reinforced by the efficacy of STN inactivation in ameliorating motor symptoms in Parkinson's disease patients (Blandini et al, 1997;Limousin et al, 1995), though the possibility that mGluR-mediated responses in both GP and STN play an important role in this scenario was barely explored. However, some of the electrophysiological features of the mGluR-mediated modulation of HVA Ca 2ϩ currents-lack of desensitization, fast kinetics (as classical membrane-gated modulators)-reinforces the likelihood of the physiological role of mGluRs in affecting fast responses driven by synaptically released endogenous glutamate.…”