Influence of Hypercapnia and Pharmacological Administration of the 5‐HT1A Receptor Agonist 8‐OH DPAT on Short‐ and Long‐Term Variability in Inspiratory Motor Activity in Two Parkinson's Disease Rat Models

Abstract

Parkinson's Disease is a neurological disorder primarily caused by the loss of dopaminergic (DA) neurons, and is typically characterized by both motor symptoms that include altered motor variability and dynamics, and non‐motor symptoms (NMS). Amongst these NMS, respiratory abnormalities have been noted in PD patients and multiple causes have been proposed, including impaired central respiratory control. Dysfunction in serotonergic (5‐HT) neurotransmission is becoming better appreciated for its role in the progression of the motor and NM symptoms of PD. 5‐HT signaling is important in the control of breathing, thus dysfunction may play a role in the development of respiratory abnormalities and may contribute to alterations in breathing variability. Ongoing work in our laboratory has focused on characterizing the respiratory phenotype of PD in 6‐hydroxydopamine (6‐OHDA) neurotoxin‐induced unilateral substantia nigra (SN)‐ and medial forebrain bundle (MFB)‐lesioned rat PD models. The goals of the current study were to assess the effects of acute administration of the 5‐HT1A receptor agonist 8‐OH‐DPAT and hypercapnia independently and in combination on short‐ and long‐term breathto‐breath variability in inspiratory motor (diaphragm EMG) activity in spontaneously breathing urethane‐anesthetized adult female rats at 2‐weeks after SN (n=7) or MFB (n=12) 6‐OHDA injections; control rats received vehicle injections (SN, n=4; MFB, n=6). Using Poincaré plot analysis, we found that 6‐OHDA lesioned rats generally had greater short‐ and long‐term variability in basal burst frequency than vehicle controls. While MFB‐injected 6‐OHDA and vehicle control rats display similar amplitude variability, both groups display lower burst frequency and amplitude variability compared to SN‐injected 6‐OHDA and vehicle control rats in all conditions. During hypercapnia, short‐ and long‐term frequency and amplitude variability are inconsistently modified across all groups. Acute 8‐OH‐DPAT injection increases short‐ and long‐term frequency variability but decreases or is ineffective in altering amplitude variability in all groups of 6‐OHDA‐ and vehicle‐injected rats and exacerbates the variability associated with their hypercapnic ventilatory responses. While these preliminary observations suggest that (compared to control rats) SN‐ and MFB‐lesioned rats exhibit differences in 5‐HT1A receptor activation‐induced amplitude and frequency variability effects, additional experiments are needed to better characterize hypercapnic influences on short‐ and long‐term variability in these models and to identify specific mechanisms underlying the observed differences.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.