AbstractAgonists of inhibitory serotonin 1A receptors (5-HT1AR) may have therapeutic potential for their ability to enhance and stabilize respiration These effects are suggested to be mediated by inhibition of inhibitory interneurons of the respiratory control network. However, precise effects of selective 5-HT1AR agonism on this network are poorly understood. The main aim of the thesis was to establish the effects of systemic 5 HT1AR transmission on respiratory motor drives, during rest and homeostatic respiratory reflexes, as generated by the intact respiratory control network in rats.
Systemic administration of selective 5-HT1AR agonist NLX-101 in rats in situ resulted in: enhanced respiratory rate due to shortening of the expiratory phase; promoted late-expiratory abdominal activity; and enhanced respiratory patterns in phrenic and abdominal, but not hypoglossal and vagal nerve motor outputs. Homeostatic respiratory reflex responses were not altered by systemic NLX-101. Fluorescent in situ hybridization indicated that 5 HT1AR RNA is present in SLC32A1-positive (i.e. glycinergic and/or GABAergic) neurones and SLC32A1-negative neurones, broadly distributed across key regions of the respiratory control network. Extracellular recordings of functionally identified respiratory neurones in the ventral respiratory column, combined with juxta-cellular pico-ejection of NLX-101, indicated that 5-HT1A R expressing neurones are also broadly distributed across functional subpopulations of respiratory neurones.
The broad expression of 5-HT1AR across anatomical regions and functional subpopulations of respiratory neurones indicates that the observed enhanced respiratory drive after systemic 5-HT1A transmission is likely an emergent network effect mediated by action at multiple neurone populations and mechanisms throughout the respiratory network. Based on the signature of functional effects of systemic NLX-101, I propose several candidate contributing mechanisms.
The thesis contributes to establishing the role of 5-HT1AR in respiratory control, and ultimately, the therapeutic potential of 5-HT1AR transmission in the reversal of opioid induced respiratory depression and the treatment of respiratory control disorders such as Rett syndrome.
|Date of Award||24 Jun 2021|
|Supervisor||Ana Paula Abdala Sheikh (Supervisor) & Sergey Kasparov (Supervisor)|