Hypoxic ventilatory response in the rats with 6-hydroxydopamine lesion of the medial forebrain bundle and peripheral dopamine receptor blockade

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.