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. 2017 Mar 27;24(1):24.
doi: 10.1186/s12929-017-0331-2.

Serotonergic system in hypoxic ventilatory response in unilateral rat model of Parkinson's disease

Kryspin Andrzejewski  1 , Katarzyna Kaczyńska  2 , Małgorzata Zaremba  3
Affiliations

Serotonergic system in hypoxic ventilatory response in unilateral rat model of Parkinson's disease

Kryspin Andrzejewski et al. J Biomed Sci. .

Abstract

Background: Malfunctioning of the serotonergic system in Parkinson's disease may contribute to non-motor symptoms such as respiratory complications. Thus the aim of our study was to investigate the role of serotonin 5-HT2 receptors in the modulation of normoxic breathing and the hypoxic ventilatory response (HVR) in rat model of Parkinson's disease.

Methods: Wistar rats were lesioned unilaterally with double 6-hydroxydopamine (6-OHDA) injection to the right medial forebrain bundle (MFB). Before lesion and two weeks later animals were put in whole body plethysmography chamber and exposed to hypoxia (8% O2). Before hypoxic tests animals received intraperitoneal injections of DOI and ketanserin. Efficacy of lesion was confirmed by cylinder test, assessing limb use asymmetry.

Results: Degeneration of the nigrostriatal pathway augmented response of tidal volume and minute ventilation to hypoxia. DOI administration in control and lesion state caused a significant rise in normoxic respiratory rate and minute ventilation. Yet, ventilatory response of these parameters to hypoxia was attenuated. Post-DOI magnitude of HVR in lesioned state was decreased in compare to pre-lesion control. Subsequent ketanserin injection reverted DOI-induced respiratory effects. We demonstrated that 6-OHDA treatment decreased the content of serotonin in the injured striatum and on both sides of the brainstem, leaving the concentration of noradrenaline on unchanged level.

Conclusions: These observations showed that damage of the nigrostriatal system initiates changes in the serotonergic system, confirmed by reduced concentration of serotonin in the striatum and brainstem, which affects the magnitude of respiratory response to hypoxia after activation of 5-HT2 receptors.

Keywords: 6-OHDA rat model; DOI; Hypoxia; Ketanserin; Serotonergic 5-HT2 receptors.

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Figures

Fig. 1
Fig. 1
Scheme of the experimental protocol in 6-OHDA lesioned rats
Fig. 2
Fig. 2
Effects of vehicle (SHAM) or 6-OHDA injection to the MFB on hypoxic respiratory responses of VT (a, d), respiratory rate (b, e) and minute ventilation (c, f). The data are expressed as percentage of change in reference to normoxic value considered as 100%. All values are means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001, versus the respective pre-hypoxic value; # P < 0.05, ## P < 0.01, versus the corresponding pre-lesion value; (n = 5 (vehicle group), n = 9 (6-OHDA group))
Fig. 3
Fig. 3
Effects of i.p. injection of DOI and ketanserin on tidal volume (a), frequency of breathing (b) and minute ventilation (c) in normoxic condition in the intact rats and two weeks after lesion with 6-OHDA. All values are means ± SEM. *P < 0.05 versus the respective control value; ***P < 0.001, versus the respective control and post-ketanserin values. # P < 0.05, ## P < 0.01, versus the corresponding value before and after 6-OHDA treatment (n = 9)
Fig. 4
Fig. 4
Effects of i.p. injection of DOI and ketanserin on tidal volume response to hypoxia in the intact rats (a) and two weeks after lesion with 6-OHDA (b). Effects of i.p. injection of DOI and ketanserin on frequency of breathing response to hypoxia in the intact state (c) and two weeks after lesion (d). Effects of i.p. injection of DOI and ketanserin on minute ventilation response to hypoxia in the intact rats (e) and two weeks after lesion with 6-OHDA (f). The data are expressed as percentage of change in reference to normoxic value considered as 100%. All values are means ± SEM. *P < 0.05, ***P < 0.001, versus the respective pre-hypoxic baseline value; # P < 0.05, ## P < 0.01, ### P < 0.001, versus the corresponding control and post-ketanserin value; + P < 0.05, ++ P < 0.01, versus the corresponding post-ketanserin value (n = 9)
Fig. 5
Fig. 5
Concentration of serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA) (a, b) and 5-HIAA/5-HT turnover (c) in respective left (L) and right (R) brain structures (striatum and brainstem) in sham and 6-OHDA treated rats evaluated by HPLC detection ex vivo. All values are means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, comparison between sham and 6-OHDA treated groups (n = 8–9/per group)
Fig. 6
Fig. 6
Effects of 6-OHDA injection on incidence of ipsilateral and contralateral to lesion forepaw usage. 6-OHDA application caused preference to use the right forelimb, ipsilateral to lesioned right MFB during rearing and landing in the cylinder test. All values are means ± SEM. *P < 0.05, versus the use of left or right forepaw in 6-OHDA treated state; # P < 0.05, between pre- and post-lesion states
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