Effects of Fluoxetine on Inspiratory Motor Activity and Chemical Control of Breathing in Spontaneously Breathing Urethane‐Anesthetized 6‐OHDA MFB‐lesioned Parkinson’s Disease Rat Model

Abstract

Breathing abnormalities are a common non‐motor symptom (NMS) of Parkinson’s Disease (PD), and multiple causes have been proposed, including impaired central respiratory control. While the loss of dopaminergic neurons is the primary pathology of PD, it is becoming better appreciated that serotonergic (5‐HT) dysfunction also plays a role in the development of motor and NMS and complications in PD. To this end, recent studies addressing the role of 5‐HT in PD symptoms have revealed that activation or antagonism of specific 5‐HT receptor subtypes may have therapeutic benefit. 5‐HT neurotransmission is also known to play a critical role in control of breathing; thus, respiratory abnormalities in PD may be further complicated by the progressive 5‐HT dysfunction in PD. Ongoing work in our laboratory has been focused on characterizing the respiratory phenotype of PD using 6‐hydroxydopamine (6‐OHDA) neurotoxin‐induced preclinical rat models of PD. Here, we evaluate potential contributions of 5‐HT dysfunction by assessing the effects of acute administration of the selective 5‐HT reuptake inhibitor fluoxetine hydrochloride (FLX) on basal inspiratory motor (diaphragm EMG) activity and hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses in spontaneously breathing urethane‐anesthetized adult female rats 2‐weeks after unilateral medial forebrain bundle (MFB) 6‐OHDA or vehicle/control injection. Basal (BL) diaphragm EMG activity was recorded for ≥30 min, the HVR (12% O2, 90s) and HCVR (7% CO2, 5 min) were assessed, acute FLX (10 mg/kg, iv) was injected and allowed 30 min to exert steady‐state effects, and then the HVR and HCVR were re‐assessed. We found that in both vehicle‐ and 6‐OHDA‐injected rats, administration of FLX produced an initial increase in burst frequency (by ~30%) and amplitude (by ~15%) above BL levels within ~60 s, after which burst frequency attenuated to a new steady‐state level of ~10% above BL levels while burst amplitude returned to slightly below BL levels in vehicle‐injected rats, but attained a new steady‐state level of ~10% above BL levels in 6‐OHDA‐injected rats. The effects of FLX on HVR and HCVR frequency behaviors were negligible in both control‐ and 6‐OHDA‐injected rats although a slight attenuation of the HVR frequency increase (by ~5%) was seen. The effects of FLX on HVR and HCVR amplitude behaviors, while underpowered, showed a trend of slightly enhanced of HVR amplitude (by ~5%) and HCVR amplitude (by ~9%) in 6‐OHDA‐injected rats; however, additional experiments are needed to determine the significance of these observations. While these preliminary observations suggest that (compared to control rats) MFB‐lesioned rats exhibit a difference in FLX‐induced effects on basal inspiratory burst amplitude alterations, acute FLX administration may not be able to fully correct chemical control of breathing deficits. We suggest that additional experiments are needed to better identify specific 5‐HT mechanisms that may contribute to chemical control of breathing deficits in this PD rat model.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson’s Disease Research at Stony Brook University