Neurotransmitters in central respiratory control

Abstract

A diverse group of processes are involved in central control of ventilation. Both fast acting neurotransmitters and slower acting neuromodulators are involved in the central respiratory drive. This review deals with fast acting neurotransmitters that are essential centrally in the ventilatory response to H⁺/CO₂ and to acute hypoxia. Data are reviewed to show that the central response to H⁺/CO₂ is primarily at sites in the medulla, the most prominent being the ventral medullary surface (VMS), and that acetylcholine is the key neurotransmitter in this process. Genetic abnormalities in the cholinergic system lead to states of hypoventilation in man and that knock out mice for genes responsible for neural crest development have none or diminished CO₂ ventilatory response. In the acute ventilatory response to hypoxia the afferent impulses from the carotid body reach the nucleus tractus solitarius (NTS) releasing glutamate which stimulates ventilation. Glutamate release also occurs in the VMS. Hypoxia is also associated with release of GABA in the mid-brain and a biphasic change in concentration of another inhibitory amino acid, taurine. Collectively changes in these amino acids can account for the ventilatory output in response to acute hypoxia. Future studies should provide more data on molecular and genetic basis of central respiratory drive and the role of neurotransmitter in this essential function.

Introduction

A diverse group of biophysical and biochemical processes in the central nervous system are involved in initiating respiratory rhythm and respiratory depth which collectively we call central ventilatory drive. These processes in the central nervous system are influenced by and respond to changes in oxygen tension, CO₂ tension, and hydrogen ion concentration. The exact mechanisms of transduction of signals for these events have been the subject of intense study in the past two decades or so. More recently, it has become apparent that a number of neurotransmitters centrally are involved in these processes. Changes in CO₂ and O₂ tension also affect brain metabolism and hydrogen ion homeostasis and thus modify the central respiratory drive, where a number of amino acid neurotransmitters change their concentration in the brain as part of CO₂ fixation in the Krebs cycle (Kazemi and Hoop, 1991). In the ventilatory response to acute hypoxia there is evidence to support a significant role centrally for fast-acting amino acid neurotransmitters, as well as slower-acting neuromodulators and modifiers.

The effect of neurotransmitters centrally on ventilatory drive in general parallel their effects on neuronal function. Excitatory neurotransmitters stimulate ventilation and inhibitory ones depress ventilation. Among neurotransmitters are amino acids such as glutamate, GABA, taurine and glycine, and neuromodulators such as adenosine, serotonin, dopamine, substance-P and in an entirely different category, acetylcholine. Receptors for many of these neurotransmitters have been identified in the brain in respiratory related nuclei, particularly in the mid-brain. There have been extensive reviews on neurotransmitters and central control of ventilation in the past 5 years and some of the mechanisms of neuronal interactions are detailed in these reviews (Bonham, 1995, Bianchi et al., 1995).

Many of these neurotransmitters centrally affect both respiratory drive and cardiac function in the same direction and two of the amino acid neurotransmitters, glutamate and GABA, influence whole body O₂ consumption and CO₂ production (Chiang et al., 1986, Kneussl et al., 1986a, Kneussl et al., 1986b). For example, glutamate centrally increases minute ventilation, cardiac output and O₂ consumption and GABA the reverse.

Since respiratory control is critical to CO₂ and O₂ homeostasis, in this article we will concentrate primarily on central neurotransmitters in the ventilatory response to CO₂ and H⁺, and in a separate section, we will review the data on amino acid neurotransmitters in the ventilatory response to hypoxia, particularly the acute response.