Phrenic and hypoglossal nerve activity during respiratory response to hypoxia in 6-OHDA unilateral model of Parkinson's disease.

AIMS: Parkinson's disease (PD) patients apart from motor dysfunctions exhibit respiratory disturbances. Their mechanism is still unknown and requires investigation. Our research was designed to examine the activity of phrenic (PHR) and hypoglossal (HG) nerves activity during a hypoxic respiratory response in the 6-hydroxydopamine (6-OHDA) model of PD. MAIN METHODS: Male adult Wistar rats were injected unilaterally with 6-OHDA (20µg) or the vehicle into the right medial forebrain bundle (MFB). Two weeks after the surgery the activity of the phrenic and hypoglossal nerve was registered in anesthetized, vagotomized, paralyzed, and mechanically ventilated rats under normoxic and hypoxic conditions. Lesion effectiveness was confirmed by the cylinder test, performed before the MFB injection and 14days after, before the respiratory experiment. KEY FINDINGS: 6-OHDA lesioned animals showed a significant increase in normoxic inspiratory time. Expiratory time and total time of the respiratory cycle were prolonged in PD rats after hypoxia. The amplitude of the PHR activity and its minute activity were increased in comparison to the sham group at recovery time and during 30s of hypoxia. The amplitude of the HG activity was increased in response to hypoxia in 6-OHDA lesioned animals. The degeneration of dopaminergic neurons decreased the pre-inspiratory/inspiratory ratio of the hypoglossal burst amplitude during and after hypoxia. SIGNIFICANCE: Unilateral MFB lesion changed the activity of the phrenic and hypoglossal nerves. The altered pre-inspiratory hypoglossal nerve activity indicates modifications to the central mechanisms controlling the activity of the HG nerve and may explain respiratory disorders seen in PD, i.e. apnea.

Respiratory activity in the 6-hydroxydopamine model of Parkinson's disease in the rat.

Respiratory disturbances accompany Parkinson's disease. Weakness of the respiratory muscles or lowering of central respiratory drive might be responsible for respiratory disability. Striatal injection of 6-hydroxydopamine (6-OHDA) simulates motor symptoms of Parkinson's disease in the rat. Present study investigated whether unilateral infusion of 6-OHDA into the striatum may evoke respiratory disorders and therefore be a model for the study of the respiratory aspects of Parkinson's disease. Two weeks after the infusion the animals were anesthetized, vagotomized, paralyzed and artificially ventilated. Neural respiratory activity in the vehicle and 6-OHDA treated groups of animals was assessed from the peak amplitude of the phrenic and hypoglossal bursts, frequency of bursts and minute activity during baseline ventilation and acute intermittent hypoxia composed of five 1.5 minute long episodes of 11 percent oxygen introduced every 3 minutes. An impairment of dopaminergic pathways by 6-OHDA evoked separate effects on phrenic and hypoglossal activity. Under baseline conditions the respiratory parameters taken from the integrated phrenic nerve activity unchanged, while the preinspiratory part of the hypoglossal activity (pre-I HG) was reduced both in terms of its onset and amplitude. 6-OHDA did not affect the phrenic response to acute intermittent hypoxia but it increased the hypoglossal response (Fig. 2). Hypoxia activated the pre-I HG in both experimental groups. Although the pre-I HG increased strongly during hypoxic stimulation, the ratio of the pre-inspiratory hypoglossal amplitude to the inspiratory hypoglossal amplitude never achieved similar values as in the sham group. This ratio decreased significantly during secondary decline of the hypoxic respiratory response. A decline of the hypoxic response was more intense in the hypoglossal activity than in the phrenic activity and moved into hypoxic apnoea more frequently in the Parkinson's disease model. The results indicate a differential modulation of the phrenic and hypoglossal neural output with increased chemical drive when dopaminergic pathways were impaired by 6-OHDA suggesting that such a mechanism may contribute to respiratory insufficiency in Parkinson's disease. An involvement of a modified mechanism of dopamine efflux and of serotonin and orexin during hypoxia is suggested in the observed changes in the hypoglossal activity in the 6-OHDA model of PD.