Effects of Acute Administration of a Serotonin (5-HT)_1BReceptor Agonist on Breathing Abnormalitiesin SN 6-OHDA-induced Rat Model of Parkinson’s Disease

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 result, at least in part, from impaired central respiratory neural control, and manifest as alterations in spontaneous breathing patterns as well as deficits in the ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). While the primary neuropathology of PD is related to the loss of dopaminergic neurons in the nigrostriatal pathway, serotonergic system (5-HT) dysfunction also appears to play a role in the development of some motor and NMS and complications in PD. Since the 5-HT system is well known to play a critical role in neural control of breathing, breathing abnormalities in PD may result from or be further complicated by 5-HT system dysfunction. In support of this possibility, ongoing studies in our laboratory using a preclinical rat model of PD produced by unilateral injection of the neurotoxin 6-OHDA directly into the substantia nigra (SN) show that acute administration of 5-HT 1A receptor agonists can partially or fully correct PD-related HCVR frequency and amplitude deficits but are ineffective in improving PD-related HVR deficits. Here, we evaluated potential contributions of 5-HT 1B receptor (5-HTR 1B )-mediated dysfunction to PD-related breathing abnormalities by examining the effects of acute administration of the FDA-approved 5-HTR 1B agonist Zolmitriptan (ZOL; 5.6 mg/kg, iv) on diaphragm EMG activity during basal breathing (BL; 40% O 2 ), acute hypoxic exposure (12% O 2 , 90s), and acute hypercapnic exposure (7% CO 2 , 5 min) in spontaneously breathing urethane-anesthetized adult female rats at 2-weeks after unilateral SN 6-OHDA injection (n=9). Administration of ZOL produced fairly negligible effects on BL breathing timing and patterning behaviors, with the measured parameters being modified ‘up or down’ from pre-ZOL levels by ≤0.7-5.8% (P≥0.2). For the HVR, an enhancement of the frequency increase by an additional 5.9%, 5.0%, and 9.7% (p<0.001) at 30s, 60s, and 90s during the hypoxic exposure, respectively, was observed albeit the blunted PD-related HVR amplitude increase was variably affected with some rats continuing to exhibit a return to near BL amplitude levels before the hypoxic exposure was completed. Moreover, the post-hypoxic frequency decline was slightly exaggerated and prolonged while the post-hypoxic amplitude decline was delayed. For the HCVR, the blunted PD-related frequency increase and early stages of the blunted PD-related amplitude increase were unaffected; however, in contrast to the amplitude increase pre-ZOL which began to wane before the end of the hypercapnic exposure, the amplitude increase post-ZOL was sustained and slightly enhanced by an additional 3.8%, (P=0.039) at 5-min during hypercapnia. While additional experiments are needed to more comprehensively evaluate 5-HTR 1B -mediated contributions to breathing abnormalities in PD, the current findings suggest that 5-HTR 1B agonist treatment may slightly improve some deficits in hypoxic and hypercapnic chemical control of breathing. Thomas Hartman Center for Parkinson's Disease Research at Stony Brook University This abstract was presented at the American Physiology Summit 2025 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.