Serotonin (5-HT)-1A receptor activation alters heart rate variability (HRV) in SN 6-OHDA-induced rat model of Parkinson's Disease

Parkinson’s disease (PD) is a multifaceted progressive neurodegenerative disease that includes a broad range of motor and non-motor symptoms (NMS). Autonomic nervous system (ANS) dysfunction is associated with a number of common NMS in PD that exert a profound impact on quality of life and increase the risk of mortality. ANS dysfunction, which likely precedes the onset of motor symptoms, includes changes in heart rate variability (HRV) that reflect pathological adjustments in the balance between sympathetic (SNS) and parasympathetic (PNS; vagal) influences on heart rate control. While the primary neuropathology of PD is related to the loss of dopamine neurons in the nigrostriatal pathway, serotonergic (5-HT) dysfunction also appears to play a role in the development of some motor and NMS and complications in PD. 5-HT is also known to play a critical role in cardiovascular (cardiac) regulation; thus, autonomic dysfunction in PD may be further complicated by 5-HT dysfunction. To begin to address this possibility, we investigated HRV quantified from 5-min segments of continuously recorded ECG activity before and after acute systemic administration of the 5-HT 1A receptor agonist 8-OH-DPAT (DPAT) in urethane-anesthetized adult female rats at 2-weeks after unilateral injection of the neurotoxin 6-OHDA (n=11) or vehicle (VEH; n=7) directly into the substantia nigra (SN). HRV measures evaluated included standard deviation (SD) of R-R intervals (SDRR) and root mean square of successive differences in R-R (RMSSD) as time-domain measures; absolute (abs) and normalized (nu) low-frequency (LF: 0.2-0.75 Hz) and high-frequency (HF: 0.75-3.0 Hz) spectral power and the LF/HF ratio as frequency domain measures; and Poincaré plot SD perpendicular to (SD1) and along (SD2) the line of identity and the SD1/SD2 ratio as non-linear measures. For these analyses, SDRR, LF, and SD2 were considered indices of mixed cardiac SNS and PNS activity; RMSSD, HF, and SD1 were considered indices of PNS activity; and LF/HF and SD1/SD2 were considered indices of sympatho-vagal balance. Before DPAT (compared to VEH-injected rats), 6-OHDA-injected rats exhibited slightly but not significantly higher HR and lower SDRR, RMSSD, abs and nu LF power, abs HF power, LF/HF ratio, SD1, and SD2, but the R-R interval, nu HF power, and SD1/SD2 ratio were similar between the groups. Following DPAT administration, both 6-OHDA- and VEH-injected rats exhibited significantly reduced HR by ~15% and increased R-R intervals by 20%. In 6-OHDA-injected rats, DPAT also increased SDRR, RMSSD, abs HF power, SD1, and the SD1/SD2 ratio but significantly reduced nu HF power; similar trends were noted in VEH-injected rats. These data demonstrate that while most HRV measures are minimally altered under baseline conditions, 5-HT 1A receptor activation can significantly alter autonomic balance and HRV metrics (especially measures associated with PNS activity) in the SN 6-OHDA-induced lesion rat model of PD. NIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.