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. 2024 Apr 17;25(8):4403.
doi: 10.3390/ijms25084403.

Impact of Serotonergic 5HT1A and 5HT2A Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson's Disease

Kryspin Andrzejewski  1 , Magdalena E Orłowska  1 , Małgorzata Zaremba  2 , Ilona Joniec-Maciejak  2 , Katarzyna Kaczyńska  1
Affiliations

Impact of Serotonergic 5HT1A and 5HT2A Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson's Disease

Kryspin Andrzejewski et al. Int J Mol Sci. .

Abstract

In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT1A and 5-HT2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO2 in O2) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO2 and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT1AR agonist 8-OH-DPAT and 5-HT2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.

Keywords: 5-HT2AR; 6-OHDA model; Parkinson’s disease; apnea; hypercapnia; respiratory disorders; serotonin.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Tidal volume (A), frequency of breathing (B) and minute ventilation (C) during air breathing (normocapnia) and ventilatory response to hypercapnia in Sham (blue line) and 6-OHDA-treated rats (red line). Differences between Sham and 6-OHDA groups were assessed using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare the response to hypercapnia and recovery time (R) with control values during normocapnia (C). The data are presented as mean ± SEM; *** p < 0.001 vs. normocapnia control value, # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 6-OHDA-treated group (n = 20 per group).
Figure 2
Figure 2
Tidal volume (A,B) and frequency of breathing (C,D) during air breathing (normocapnia) and ventilatory response to hypercapnia in Sham (blue line) and 6-OHDA rats (red line) treated with i.p. injection of 8-OH-DPAT (dashed lines). Differences between Sham and 6-OHDA groups were assessed using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare the response to hypercapnia and recovery time (R) with control values during normocapnia (C). The data are presented as mean ± SEM; * p < 0.05, vs. normocapnia control value, # p < 0.05, ## p < 0.01, vs. 8-OH-DPAT untreated state (n = 6 per group).
Figure 3
Figure 3
Minute ventilation (A,B) during air breathing (normocapnia) and ventilatory response to hypercapnia in Sham ((B), blue line) and 6-OHDA-treated rats ((A), red line) treated with i.p. injection of 8-OH-DPAT (dashed lines). Minute ventilation (C,D) reactivity to hypercapnia expressed as a percentage of baseline (normocapnia) in Sham ((D), blue line) and 6-OHDA-treated rats ((C), red line) treated with i.p. injection of 8-OH-DPAT (dashed lines). Two-way ANOVA followed by the Newman-Keuls post hoc test was used to analyze the data presented in panels (A,B). Data presented in panels (C,D) were evaluated using the Mann-Whitney U test (differences between Sham and 6-OHDA groups) and the Wilcoxon signed-rank test to compare hypercapnia response and recovery time (R) with control values during normocapnia (C). The data are presented as mean ± SEM; * p < 0.05, *** p < 0.001 vs. normocapnia control value, ## p < 0.01, ### p < 0.001, vs. 8-OH-DPAT untreated state (n = 6 per group).
Figure 4
Figure 4
Tidal volume (A,B) and frequency of breathing (C,D) during air breathing (normocapnia) and ventilatory response to hypercapnia in Sham (blue line) and 6-OHDA rats (red line) treated with i.p. injection of 25CN-NBOH (dashed lines). Differences between Sham and 6-OHDA groups were assessed using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare the response to hypercapnia and recovery time (R) with control values during normocapnia (C). The data are presented as mean ± SEM; * p < 0.05, vs. normocapnia control value, ## p < 0.01, ### p < 0.001, vs. 25CN-NBOH untreated state (n = 7 per group).
Figure 5
Figure 5
Minute ventilation (A,B) during air breathing (normocapnia) and ventilatory response to hypercapnia in Sham ((B), blue line) and 6-OHDA-treated rats ((A), red line) treated with i.p. injection of 8-OH-DPAT (dashed lines). Minute ventilation (C,D) reactivity to hypercapnia expressed as a percentage of baseline (normocapnia) in Sham ((D), blue line) and 6-OHDA-treated rats ((C), red line) treated with i.p. injection of 25CN-NBOH (dashed lines). Two-way ANOVA followed by the Newman-Keuls post hoc test was used to analyze the data presented in panels (A,B). Data presented in panels (C,D) were evaluated using the Mann-Whitney U test (differences between Sham and 6-OHDA groups) and the Wilcoxon signed-rank test to compare hypercapnia response and recovery time (R) with control values during normocapnia (C). The data are presented as mean ± SEM; * p < 0.05, *** p < 0.001 vs. normocapnia control value, # p < 0.05, ## p < 0.01, ### p < 0.001, vs. 25CN-NBOH untreated state (n = 7 per group).
Figure 6
Figure 6
Tidal volume (A,B) and frequency of breathing (C,D) during air breathing (normocapnia) and ventilatory response to hypercapnia in Sham (blue line) and 6-OHDA rats (red line) treated with i.p. injection of TCB-2 (dashed lines). Differences between Sham and 6-OHDA groups were assessed using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare the response to hypercapnia and recovery time (R) with control values during normocapnia (C). The data are presented as mean ± SEM; * p < 0.05, vs. normocapnia control value, # p < 0.05, ## p < 0.01, ### p < 0.001, vs. TCB-2 untreated state (n = 7 per group).
Figure 7
Figure 7
Minute ventilation (A,B) during air breathing (normocapnia) and ventilatory response to hypercapnia in Sham ((B), blue line) and 6-OHDA-treated rats ((A), red line) treated with i.p. injection of TCB-2 (dashed lines). Minute ventilation (C,D) reactivity to hypercapnia expressed as a percentage of baseline (normocapnia) in Sham ((D), blue line) and 6-OHDA-treated rats ((C), red line) treated with i.p. injection of 25CN-NBOH (dashed lines). Two-way ANOVA followed by the Newman-Keuls post hoc test was used to analyze the data presented in panels (A,B). Data presented in panels (C,D) were evaluated using the Mann-Whitney U test (differences between Sham and 6-OHDA groups) and the Wilcoxon signed-rank test to compare hypercapnia response and recovery time (R) with control values during normocapnia (C). The data are presented as mean ± SEM; * p < 0.05, ** p < 0.01, *** p < 0.001, vs. normocapnia control value, # p < 0.05, ## p < 0.01, ### p < 0.001, vs. TCB-2 untreated state (n = 7 per group).
Figure 8
Figure 8
Minute ventilation during air breathing (normocapnia) and ventilatory response to hypercapnia in 6-OHDA treated rats treated with i.p. injection of 8-OH-DPAT (A), 25CN-NBOH (B), TCB-2 (C) (red line, dashed) and Sham untreated rats (blue line). Two-way ANOVA followed by the Newman-Keuls post hoc test was used to analyze the data. C stands for control value; R indicates return after hypercapnia. The data are presented as mean ± SEM; * p < 0.05, *** p < 0.001, vs. normocapnia control value, # p < 0.05, ## p < 0.01, vs. Sham untreated rats (n = 7 per group).
Figure 9
Figure 9
Apnea incidence (A) and duration (B) in Sham and 6-OHDA-treated rats. Student’s t-test was used to analyze differences between 6-OHDA and Sham groups, ## p < 0.01, vs. Sham rats (n = 8–10 per group).
Figure 10
Figure 10
Concentration of biogenic amines in the striatum (A–C) and brainstem (D–F) of Sham and 6-OHDA-treated rats. The content of dopamine (DA), noradrenaline (NA), serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) was assessed by HPLC detection ex vivo and expressed as pg mg−1 of fresh tissue. Student’s t-test was used to analyze differences between the 6-OHDA and Sham groups. The data are expressed as mean ± SEM. # p < 0.05, ## p < 0.01, ### p < 0.001—significance between both groups (n = 16–18 per group).
Figure 11
Figure 11
Diagram visualizing animal groups, procedures and treatment on a timeline.
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