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Motor disorders present in patients with Parkinson’s disease (PD) can be mimicked in animals by striatal injection of 6-hydroxydopamine (6-OHDA) that causes a destruction of the dopaminergic nigrostriatal neurons. Since respiratory disturbances accompany PD, the aim of this study was to investigate whether 6-OHDA lesion in the striatum could elicit changes in ventilation and in ventilatory response to hypoxia. Experiments were performed on adult rats that received a microinjection of 6-OHDA or vehicle into the right striatum stereotaxically. Before and 14 days post striatal injection conscious rats were placed in whole body plethysmograph to measure ventilatory parameters as tidal volume, frequency of breathing and minute ventilation during eupnoea and ventilatory response to 3 minutes breathing with 8% hypoxic gas mixture. The hypoxic test was preceded by a behavioral cylinder test to check whether the 6-OHDA lesion was effective in evoking a motor deficit. After the 6-OHDA injection the cylinder test demonstrated a clear preference of the use of the forelimb ipsilateral to the 6-OHDA lesion during rising on the wall of cylinder. The pattern of lung ventilation after the lesion resembled that of the control animals. Breathing with 8% oxygen evoked characteristic hypoxic hyperventilatory response; however in 6-OHDA-lesioned animals mean tidal volume increased more in response to hypoxia than in controls and attained significantly higher amplitude during the first minute of the hypoxic exposure. In conclusion, studies revealed that an increase in chemical drive for respiration due to hypoxia changed the hypoxic ventilatory response in 6-OHDA model of PD. Since dopamine is thought to exert an inhibitory influence on respiratory hypoxic response, an increase of hypoxic hyperventilation following 6-OHDA injection might result from a deficit of dopamine due to degeneration of dopaminergic neurons evoked by 6-OHDA.
Besides extrapyramidal motor disorders, disturbances in breathing form an important part of the Parkinson’s disease (PD) syndrome. Respiratory disturbances include alternations in respiratory pattern, pulmonary ventilation and a dysfunction of upper-airway muscles. We investigated whether the animal model of Parkinson’s disease created by unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum induced changes in neural respiratory activity to the diaphragm and upper-airways muscles and the respiratory response to hypoxia. The respiratory effects and response to intermittent hypoxia were studied in animals after unilateral infusion of 24 µg 6-OHDA (4 µg/1µl) or 6 µl of vehiculum into the striatum. Two weeks following the infusion the rats were anesthetized, subjected to bilateral midcervical vagotomy, paralyzed and artificially ventilated. Relation between activity of the phrenic and hypoglossal nerves was analyzed during normoxic ventilation and during acute intermittent hypoxia, composed of five episodes of 11% hypoxia introduced every 3 minutes, in the control and 6-OHDA lesioned animals. Amplitude, frequency of integrated phrenic and hypoglossal nerve activity and minute phrenic and hypoglossal activity were calculated. The results showed that unilateral nigrostriatal dopaminergic destruction in the 6-OHDA model of Parkinson’s disease did not evoke an alternation of the respiratory pattern of the phrenic and hypoglossal activity in anesthetized, normoxic rats. The difference between the control and 6-OHDA lesioned animals appeared when respiratory drive increased due to hypoxia. While the magnitude of the phrenic response to each episode of hypoxia was almost unchanged in the lesioned vs. control animals, the hypoglossal hypoxic response attained significantly higher levels in 6-OHDA lesioned rats. The biphasic response to hypoxia was maintained, however, a decline of the hypoglossal hypoxic response was more emphasized in the PD model. Changes in the respiratory frequency due to hypoxia were comparable in both groups of rats. In conclusions this study reveals that central dopamine depletion elicited by unilateral infusion of 6-OHDA into the nigrostriatal region develops a modification of the respiratory hypoxic response and intensifies an asymmetry of the phrenic and hypoglossal nerve activity. Uneven hypoxic drive to the diaphragm and the muscles of upper respiratory tract is a probable cause of this modification and might be a source of respiratory disturbances in the Parkinson’s disease
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% 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 pre- inspiratory 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.
The rat model of Parkinson’s disease (PD) based on experimental impairment of nigrostriatal dopaminergic system by 6-hydroxydopamine (6-OHDA) has been elaborated to study mechanisms of respiratory disturbances associated with PD. Following striatal injection of 6-OHDA breathing with hypoxic mixture augments the hyperventilatory response to hypoxia suggesting an attenuation of the depressant effect of dopamine on ventilation. In the present study we ask whether injection of 6-OHDA into the medial forebrain bundle (MFB), that evokes more severe motor symptoms, elicits changes in the hypoxic ventilatory response and whether changes in ventilatory response to hypoxia following the unilateral dopaminergic denervation are transmitted by peripheral dopamine D2 receptors. The experiments were performed on adult rats. Ventilatory parameters: tidal volume, minute ventilation, and frequency of breathing were measured with the use of body plethysmograph method before and two weeks following unilateral, double injection of 6-OHDA into the MFB. Changes in the body weight and behavioral cylinder test were evaluated at the same time points and compared with the results obtained in sham operated rats. Effects of peripheral dopamine D2 receptor antagonist, domperidone (1 mg/ kg i.p.) on ventilation during rest breathing and during 3 minutes exposure to hypoxia (8% O2)were studied before and after 6-OHDA injection. Two weeks after 6-OHDA treatment the cylinder test showed limb use asymmetry. Body weight increased less than in animals without 6-OHDA injection. Following the MFB lesion the hyperventilatory response to hypoxia was augmented mainly by an increment of tidal volume. Before the MFB lesion the pretreament with domperidone enhanced resting ventilation and hypoxic hyperventilatory response. After 6-OHDA injection domperidone no longer altered both normoxic breathing and the hyperventilatory hypoxic response. The study shows that an impairment of dopaminergic system by MFB lesion causes comparable changes in breathing and ventilatory response to hypoxia as lesions in the other locations of the nigrostriatal pathways. In 6-OHDA model of Parkinson’s disease changes in the hypoxic ventilatory response seem to be related to a reduction of peripheral D2 dopaminergic neurotransmission involved in the control of breathing.
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