Breathing abnormalities are a common, but understudied, non-motor symptom (NMS) in Parkinson’s Disease (PD) even though respiratory complications are the most common cause of death in PD patients. Breathing abnormalities may manifest as altered breathing patterns during wakefulness and sleep as well as deficits in hypoxic (low O 2 ) and hypercapnic (high CO 2 ) ventilatory behaviors that are unrelated to muscle weakness or impaired lung function although these conditions may exacerbate respiratory deficits as the disease progresses. While the typical motor symptoms of PD are attributed to nigrostriatal dopamine (DA) system degeneration, it is becoming better appreciated that serotonin (5-HT) system dysfunction, which also occurs in PD, plays a role in the development of some motor and NMS/complications. Since the 5-HT system is well known to play a critical role in control of breathing, breathing abnormalities in PD may result from or be further complicated by progressive 5-HT system dysfunction. The current study set-out to address two goals: (1) to gain insight to breathing abnormalities associated with the ventilatory response to combined hypoxia and hypercapnia (i.e., maximal chemoreceptor stimulation ventilatory response; MCVR) and (2) to determine whether administration of the FDA-approved 5-HTR1B agonist Zolmitriptan (ZOL), which we recently demonstrated can partially or fully correct PD-related HCVR amplitude deficits, alters MCVR behaviors. To accomplish this, at 2-weeks after unilateral substantia nigra (SN) injection of the ‘classic’ neurotoxin 6-OHDA, we examined diaphragm EMG activity in spontaneously breathing urethane-anesthetized adult female rats in response to combined acute hypoxic/hypercapnic exposure (MCVR: 12% O 2 / 7% CO 2 , 3min) before and after systemic administration of ZOL (5.6 mg/kg, iv; n=6) or vehicle (VEH, 15% DMSO in saline; n=6). Relative to basal (BL) breathing levels, baseline MCVR behaviors included a sustained robust increase in burst frequency by ~40% (pre-ZOL) and ~50% (pre-VEH) and an initial increase in amplitude by ~20% (pre-ZOL) and ~35% (pre-VEH) that slightly waned over the course of the 3min exposure duration. Surprisingly, the magnitude of the MCVR frequency increase and initial MCVR amplitude increase were similar both before and after ZOL and VEH administration; however, following ZOL, but not VEH, administration, the amplitude increase returned to BL levels before the end of the 3min exposure duration. While additional experiments are needed to more thoroughly evaluate the extent of variability in MCVR frequency and amplitude behaviors in this rat PD model as well as the potential detrimental effects of ZOL on the MCVR amplitude response, the current findings suggest that breathing abnormalities in PD also include deficits in combined hypoxic/hypercapnic chemical control of breathing Support: Thomas Hartman Center for Parkinson's Disease Research at Stony Brook University This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Lutchman et al. (Fri,) studied this question.