Glutamic acid and y-aminobutyric acid neurotransmitters in central control of breathing HOMAYOUN

KAZEMI

AND

BERNARD

HOOP

Medical Services (Pulmonary and Critical Care Unit), Massachusetts and Harvard Medical School, Boston, Massachusetts &?I14

General Hospital

KAZEMI,HOMAYOUN,AND BERNARD HOOP. Ghtamicacidandy-aminobutyric acid neurotransmitters in central control of breathing. J. Appl. Physiol. 70(l): l-7, 1991.-We review recent cross-disciplinary experimental

and theoretical investigations on metabolism of the amino acid neurotransmitters glutamic acid and y-aminobutyric acid (GABA) in the brain during hypoxia and hypercapnia and their possiblerole in central control of breathing. The roles of classicalmodifiers of central chemical drive to breathing (H+ and cholinergic mechanisms)are summarized. A brief perspective on the current widespread interest in GABA and glutamate in central control is given. The basic biochemistry of these amino acids and their roles in ammonia and bicarbonate metabolism are discussed.This review further addressesrecent work on central respiratory effects of inhibitory GABA and excitatory glutamate. Current understanding of the sites and mechanismsof action of these amino acidson or near the ventral surface of the medulla is reviewed. We focus particularly on tracer kinetic investigations of glutamatergic and GABAergic mechanismsin hypoxia and hypercapnia and their possible role in the ventilatory response to hypoxia. We conclude with some speculative remarks on the critical importance of these investigations and suggest specific directions of research in central mechanismsof respiratory control. amino acid neurotransmitters; central control of ventilation; chemoreception

of biophysical and biochemical processes at the cellular level in the central nervous system (CN 9 initiates the generation of energy required for neuronal firing to set the resting level of breathing, which we define as the central ventilatory drive. These same processes also have significant effects on central regulation or control of breathing. A number of these processes that relate to H+ and electrolyte regulation as well as CO, have been discussed in detail in recent reviews (31, 32). In this review we look at the possible role of substances other than simple electrolytes in the CNS that have a modulating effect on central ventilatory drive. In particular, we concentrate on two amino acid neurotransmitters, glutamate and y-aminobutyric acid (GABA), that affect ventilation centrally. The review addresses the metabolism of these amino acids in the CNS in hypoxia and hypercapnia and attempts to relate these events to central ventilatory drive. In general terms, effects sf amino acids on ventilation A DIVERSITY

U161-7567/91

$1.50 Copyright

parallel their effects on neuronal function. Excitatory amino acids stimulate ventilation, and inhibitory amino acids depress ventilation. Among the simple and common excitatory amino acids are aspartate and glutamate, and among the inhibitory ones are GABA, glytine, and taurine. Of these amino acids, two may be particularly relevant to central ventilatory drive, namely, glutamate and GABA. These two amino acids are intimately related to CO, fixation and H+ metabolism in the brain and are derived from the same amino acid, glutaand they have mine. Their metabolism is interrelated, opposite and profound effects centrally on ventilatory and cardiovascular functions. Specifically, glutamate may well be the key central neurotransmitter released with stimulation of afferents from peripheral chemoreceptors (25, 29). Therefore three key aspects of the amino acid neurotransmitters glutamate and GABA are reviewed. The first is the dynamics of brain ammonia metabolism and CO, fixation and their relationship to

0 1991 the American

Physiological

Society

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BRIEF REVIEW

formation and degradation (turnover rates) of brain GABA and glutamate in hypercapnia and hypoxia. The second is the effect of centrally administered GABA and glutamate on ventilatory and cardiovascular functions as well as on metabolism at large. The third is more speculative and offers an interpretation of the data from whole brain to a possible role for these two neurotransmitters in central control of breathing. Central Chemical

GLUTAMATE

GLUTAMATEGABA

Culntrol of Ventilation

The central ventilatory drive in biochemical terms has been attributed to the acidity of fluids bathing certain regions of the ventral surface of the medulla (32, 47), where [H+] in brain interstitial fluid (ISF) at these sites has been the primary determinant of the central drive. [H+] in the brain, and thus central ventilatory drive, can be altered directly by certain amino acid neurotransmitters that are directly involved in H+ metabolism via metabolism of the simplest physiochemical buffers of H+, e.g., ammonia and bicarbonate (26). Two amino acids that are intimately associated with CO, fixation in the brain are glutamate and GABA, which in addition have their own independent effects on ventilation. Other substances that do not directly affect [H+] in the CNS can also affect the central drive of ventilation, and among them are peptides, hormones, and opioids (9, 46). Recent investigations also suggest that the central effect of H+ on ventilation is related to cholinergic mechanisms (4, 5, 13, 18, 43). Metabolic activities of brain cells that affect ionic composition and H+ homeostasis in cerebral fluids are important to central ventilatory drive. The brain generates some ammonia as part of its normal metabolism, and some of the CO, it produces is fixed into the citric acid cycle (51). Brain ammonia concentration is increased during hypercapnia (53). The increase in brain ammonia is probably from within brain cells, and the increase helps buffer H+ by the reaction NH, + H+ --) NH:, increasing the strong ion difference and allowing for more HCO, to be formed. This eontribution, however, is relatively small (54), but because ammonia is a central respiratory stimulant, it helps increase the central drive in hypercapnia where it is otherwise depressed because of the compensatory CNS HCO; increase. Ammonia metabolism is associated with changes in specific amino acids such as glutamine and glutamate, as well as GABA, where the latter two have direct effects on central ventilatory drive. Amino Acid Neurotransmitter and Breathing

Metabolism.

Effects of amino acid neurotransmitters on central respiratory drive roughly parallel their excitation or inhibition of neurons (41, 42). Electrophysiological and neuroanatomic studies have demonstrated that diverse groups of neurons comprise a central pattern generator responsible for respiratory rhythm (37,48). The amino acids glutamate and GABA have opposing effects on neuronal excitation and are particularly relevant because they are directly related to CO, metabolism and

Transmitter

+ Receptor Site -

Activated

Receptor

FIG. 1. Schematic diagram of glutamate amidation to glutamine in glial cells and its movement into an adjacent presynaptic nerve ending for other metabolic processes or for synthesis of neurotransmitters glutamate and y-aminobutyric acid (GABA). Glutamate released into synaptic clefts can then interact with receptor sites on or associated with postsynaptic neurons, which results in changes in respiratory neuronal excitation, thus altering ventilation (tidal volume). Deactivation of receptors and possible dissociation of glutamate and GABA from receptors provide a mechanism by which neurotransmitter glutamate and GABA may be recycled. [From Hoop et al. (28).]

fixation in the brain. CO, enters the citric acid (Krebs) cycle through pyruvic acid and, in the process, affects the levels of aspartate, glutamate, and GABA, as well as the neutral amino acid glutamine. GABA and glutamate affect central ventilatory and cardiovascular control (15, 17), and their concentrations in the brain change during hypoxia and hypercapnia. A possible scenario for respiratory neuronal excitatory and inhibitory actions of the neurotransmitters glutamate and GABA synthesized sequentially from glutamine is presented schematically in Fig. 1. These amino acids serve as neurotransmitters in all regions of the brain, and their effect on respiration is one of many functions that they have in the CNS. The site of glutamine synthesis, from glutamate amidation via glutamine synthase (GS), is in glial cells. Glutamine thus formed can move into adjacent nerve endings where it is utilized either in metabolic pathways unrelated or not directly related to neurotransmitter glutamate and GABA synthesis or in formation of neurotransmitter glutamate and GABA via glutaminase and glutamate decarboxylase, respectively. Glutamate and GABA, when released into synaptic clefts adjacent to respiratory neurons, can bind to postsynaptic or other receptor sites, open ion channels, and thus change the polarization state or discharge rate of these neurons. Regulation of respiration can thus be determined by the interaction kinetics of glutamate and GABA with sites on receptors, as well as by the kinetics of transmitter metabolism and uptake, as outlined in Fig. 1 (28). In this schematic presentation the metabolic pathways in the CNS for these amino acids are well established, but the specific role of the glutamate-GABA interaction is a suggested mechanism based on indirect evidence. Metabolism of glutamate and GABA in the brain also relates to ammonia metabolism and furthermore indi-

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BRIEF

cates the important role that glial cells have in both amino acid metabolism and H+ homeostasis. Increase in brain ammonia is associated with a reduction in a-ketoglutarate and glutamic acid content and an increase in glutamine via the detoxification pathway for NH, (reaction I) cu-ketoglutarate

+ NH, @ GS

glutamate

+ NH,

*

glutamine

glutaminase

GS is found only in glial cells, the same cells that are essential to CO, hydration, HCO; formation, and Na+-H+ exchange in maintaining CNS acid-base balance (32). Hypercapnia is associated with an increase in brain ammonia as well as glutamine and reductions in brain glutamate and aspartate (11, 52). Brain GABA content increases in hypercapnia. These changes are important in several ways. By reducing certain acids, the H+ load in the brain is decreased, and thus there is more effeetive H+ homeostasis. One can also speculate that the increased central drive of ventilation because of the elevated [H’] is somewhat abated by the concurrent increase in GABA and fall in glutamate. This might well be an example of the important interaction between the effects of CNS [H’] and amino acid neurotransmitters in the central ventilatory drive (32). The rate of glutamate synthesis in the CNS is in good agreement with the rate at which bicarbonate is fixed into CNS glutamine. It has been shown that hypercapnia alters both CNS H+ content and CSF ammonia metabolized to glutamate and that these are linearly related. The rate of llC-labeled bicarbonate fixation into medullary tissue during l-2 h of hypercapnia increases linearly (from 0.06 t 0.01 to 0.09 t 0.03 mM/min) with CSF [H+]. In addition, mean medullary glutamine and GABA concentrations both increase significantly with a high correlation between individual values (26). Medullary glutamate concentration varies nonlinearly with cerebral metabolic rate of glucose according to a saturable kinetic process characterized by a turnover constant of 0.07 t 0.02 mM/min, which is interpreted as the rate of synthesis of endogenous glutamate for neurotzansmission in the medulla. This agrees with predicted endogenous glutamate concentration (7-10 mM) and its rate of synthesis (0.18 t 0.09 mM/min) (28). These observations clearly demonstrate that the physiological events ascribed to glutamate occur at glutamate levels that are endogenously present in the medulla under normal conditions. Eflects

of Exogenous

GABA

on Respiration

GABA depresses respiratory neurons and has a metabolism in the brain that is tied to CO, fixation and H+ metabolism. There are specific central sites where this relationship may be important (33). For example, the reticular formation in the region 3-5 mm caudal to the interaural line in the rat contains a large nucleus of small- to medium-sized GABAergic neurons (the paragigantocellular reticular nucleus) lying close to the pial

REVIEW

3

surface and with dendrites that follow the periphery of the brain stem (2). This area corresponds to the pharmacologically responsive chemosensitive area on the ventral surface of the medulla in the cat (the “intermediate” area) described by Schlaefke (47). Direct application of GABA to the ventral surface of the medulla by Yamada and colleagues (55) demonstrated that GABA is associated with reduction in ventilation and that subsequent application of the GABA antagonist bicuculline reverses the effect. The question as to whether endogenous GABA has a role was answered by the work of Hedner et al. (22), who observed a decrease in ventilation when GABA degradation in the brain was prevented by inhibition of the degrading enzyme GABA-T with aminooxyacetic acid. This fall in ventilation was similar to that seen when exogenous GABA was injected intraventricularly. This work suggests that increasing endogenous GABA by limiting its degradation had the same effect on ventilation as applying GABA exogenously. The data in these studies look at whole brain GABA or GABA applied directly to the medullary surface and do not inherently suggest that the same changes occur at the synapses under normal physiological conditions. However, they do suggest that GABAergic areas that affect ventilation are close to the ventral surface of the medulla. Appreciating these limitations of the studies, one can quantitatively support the hypothesis that a specific density of GABA-activated receptors lies on or near the ventral surface of the brain stem with projections to medullary respiratory motoneurons that, when activated, decrease tidal volume (24). There are two forms of GABA receptors on neurons, a and ,8. GABA-a-receptors are related to the Cl- channel complex and GABA-P-receptors to calcium and potassium channels. In terms of respiration, GABA-cu-receptors modulate tidal volume and P-receptors possibly modulate the pattern of breathing (50). Studies with GABA and Cl- channel blockers show that when brain cells in the presence of GABA are flooded with Cl-, cell membranes increase their Cl- flux (20, 45). Although there is no specific evidence, this phenomenon may underlie the mechanism of central depression of ventilation with GABA within specific respiratory-related neurons. A manifestation of this central ventilatory depression with GABA is to be found in the breath hold of diving animals. The freshwater turtle, for example, shows significant increases in brain GABA during a dive. With anoxia alone, brain GABA increases, but during hypoxia and hypercapnia, inhibitory taurine increases (23). GABA may affect ventilation indirectly in numerous ways, including effects on tracheal smooth muscle, where its application on ventral medullary surfaces causes bronchoconstriction (21) as well as depression of cardiovascular function (55). An increase in brain GABA reduces heart rate and may cause hypotension. In addition, an increase in CNS GABA is associated with a reduction in whole body metabolism, as reviewed below. During ventriculocisternal perfusion with GABA, whole body 0, uptake and CO, production are reduced. Thus, centrally administered GABA modulates

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BRIEF

both respiration and cardiac function and reduces whole body metabolic rate. Ventriculocisternal perfusion with GABA in dogs leads to a marked reduction in ventilation, primarily by reducing tidal volume. Inspiratory flow, one of the principal indexes of central ventilatory drive, is also reduced. Mean tidal volume decreases with onset of GABA perfusion and remains depressed during perfusion at all GABA concentrations. The fall in tidal volume vs. GABA concentration is reversible and found to be represented by a mean apparent in vivo GABA-receptor equilibrium constant of 20.5 t 8.6 mM (24). Because the equilibrium constant thus defined is inversely proportional to the forward reaction rate constant, it should be noted that, for a diffusion-limited ligand-receptor reaction, the predicted forward rate constant for cell-bound receptors is smaller than for solubilized receptors by at least three orders of magnitude, if there are 405 receptor sites per cell (8; cf. also Ref. 28). Perfusion with artificial cerebrospinal fluid (CSF) alone restores cardiorespiratory depression caused by previous GABA perfusion. Reversal of the effects of GABA almost instantly with artificial CSF suggests that receptors for GABA are close to the brain surface in contact with largecavity fluids (34). Changes in tidal volume agree quantitatively with the observation on the central effects of GABA on ventilation in rats, and effective rate constants that parameterize the change are identical in both experimental animal models (24). Efects of GABA on Metabolism With GABA-induced decrease in ventilation there is also a reduction in metabolic rates of 0, and CO2 (35). In dogs maintained at constant ventilation and perfused centrally with GABA for 15 min, mean 0, consumption and CO, production decrease by 20%. Thus, GABA when infused in the CNS depresses not only ventilation and cardiac function but also overall metabolic rate, again emphasizing the significant interrelationship between cardiorespiratory function and metabolism and the fact that physiological effects of infusing GABA centrally can be demonstrated simultaneously in several systems systemically. The reflexes and/or pathways that GABA activates in the brain that depress overall metabolism are unknown but remain worthy of investigation. Eflects of Exogenous Glutamate

on Respiration

As emphasized above, the excitatory amino acid neurotransmitter glutamate stimulates resting ventiiation by altering neuronal excitability centrally. Glutamate interacts with a number of receptor sites that are distinguished by their affinity for N-methyl-D-aspartate (NMDA) (1,12,38), kainate (16,29,40), and quisqualate. As with GABA, evidence for a relationship between the excitatory neurotransmitter glutamate and respiration Comes largely from observations of local and global changes in CNS glutamate content after experimentally induced acid-base or hypoxic changes in respiration or respiratory neuronal output. No data are available on glutamate release at the synapses, and thus again, as

REVIEW

with GABA, the role of glutamate at the cellular level in central respiratory drive remains speculative. During respiratory acidosis, increase in glutamate turnover decreases tissue glutamate concentration (27,51). In addition, there are changes in ventilation after applications of glutamate and related agonists or antagonists systemically or locally to specific neurons and areas of the brain stem identified with respiration. Iontophoretic application of glutamate onto individual respiratoryphasic medullary neurons increases neuronal activity (14, 36). It should be noted that such application, although quite local, may also affect activity of other neurons, the axons of which pass through the region of application (10). Glutamate binding sites are found in specific medullary nuclei associated with respiratory activity (39). Application of glutamate to the ventral medulla results in prompt and reversible dose-dependent increases in tidal volume (16). Glucose and glutamine are the two primary precursors of glutamate. Glutamate is synthesized by hydrolysis of glutamine or from glucose by oxidative metabolism via citric acid cycle intermediates (19). Glutamine, the predominant precursor of glutamate, is itself formed directly from glutamate and ammonia via GS (7) (cf. reaction I). Glutamine thus formed can then enter glutamatergic nerve endings, where it is sequestered from synthesis of the neurotransmitter glutamate. The central cardiorespiratory effects of glutamate have been studied using the same experimental model as for GABA (6). The results suggest that glutamate infused into the ventricular system has a significant central excitatory role in ventilation as well as hemodynamic functions and that its effects are opposite to that of centrally administered GABA. The rapidity of the responses with glutamate perfusion and their prompt reversal with mock CSF perfusion again suggest the proximity of glutamate receptors to the brain surface and to the large-cavity fluids. Efect of Endopvw-us Glutamate

on Respiration

The effects obtained with exogenously administered glutamate can also be observed by inhibiting the major biochemical pathway for glutamate metabolism to glutamine, i.e., by inhibiting GS with methionine sulfoximine (7). Inhibition of central GS is demonstrated in vivo using radiotracer [13N]ammonia incorporation into brain and CSF glutamine. Central administration of methionine sulfoximine inhibits GS in the brain, with essentially no incorporation of 13N into glutamine after inhibition of GS. Furthermore, there is a remarkable rise (>l mM) in medullary glutamate with no change in net content of glutamine. With inhibition of GS and concomitant rise in medullary glutamate, minute ventilation increases as in animals perfused with CSF containing glutamate. The effects on cardiovascular function were also similar. These studies show that exogenous application or endogenous increase in glutamate has the same effect on cardiorespiratory function.

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3RIEF

Clmeept of Central Chemoreception The ventilatory changes in response to central administration of GABA and glutamate can be interpreted in terms of simple theories of elementary chemical interactions that are governed by reaction rate constants relating the concentrations and rates of changes of concentrations of reactants. In other words, the pharmacokinetics of transmitter molecules and receptor entities on or near the ventral surface of the medulla determine quantitatively to a first approximation how resting ventilation is modified (8, 49). Fundamental to this interpretation is the widely accepted concept of chemoreception, that is, the chemical interaction mechanisms and subsequent alteration of cell membrane potential and/ or transmembrane ion conductance that underlie transmission of biologically significant information (for a detailed definition of chemoreception, see Refs. 24 and 28). Briefly, if glutamate and GABA sensitive receptor sites have the same approximate transmitter interaction geometries and the same reaction stoichiometries and lie at approximately the same depth below the ventral surface of the medulla, then the density of respiratorysensitive glutamate receptors is of the same order of magnitude as that of corresponding respiratory-sensitive GABA receptors. However, in their respective neural excitation and inhibition of ventilation, this interpretation suggests that glutamate-activated receptors apparently deactivate about an order of magnitude less frequently than GABA-activated receptors (24); thus the effect of glutamate is more long lasting than that of GABA. These observations have thus led to the postulation of the simple mechanism for the action of central glutamate and GABA on breathing shown in Fig. 1. Glutamine synthesized from glutamate and ammonia in glial cells moves into adjacent pre synaptic nerve endings for other metabolic processes or for synthesis of the neurotransmitters glutamate and GABA. These two neurotransmitters are released from their respective sites of synthesis into synaptic clefts. The sites of synthesis may or may not be within the same nerve ending or even within the same neuron. Nevertheless, glutamate and GABA molecules thus released interact with receptor sites on or associated with postsynaptic neurons. The final neural output determining the central drive related to these amino acids will then depend on the balance between excitation by glutamate and inhibition by GABA. In addition, after deactivation and subsequent dissociation of transmitter from receptor sites, recycling mechanisms can return transmitter to glial cells. It is important to emphasize that this hypothesis is based on the current knowledge of receptor binding kinetics and will require further experimental verification.

Hypoxia, VexztilatoryDrive, and Central Glutamate and GABA Brain glutamate and GABA are changed in hypoxia, and these neurotransmitters probably are important in the ventilatory and circulatory response to hypoxia. A

5

REVIEW

review of respiration and brain hypoxia has been published recently by Neubauer and associates (44). In hypoxia, O2 deprivation stimulates peripheral circulatory and respiratory chemoreceptors. Housley, Sinclair, and associates (29; personal communication, J. D. Sinclair) have demonstrated that afferent nerve fibers carry the peripheral chemoreceptor impulses to respiratory and circulatory centers, causing release of excitatory glutamate, which then increases ventilation and blood pressure. Inhibition of glutamate with specific NMDA receptor antagonist MKSOl leads to a reduction in minute ventilation during normoxia in the dog and significantly reduces the initial hyperventilation of hypoxia, suggesting that peripheral chemoreceptor stimulation with hypoxia indeed leads to central release of glutamate, which then increases minute ventilation (3). However, in severe hypoxia the cerebral metabolic pathway converting glutamate to GABA continues to function because the glutamic acid decarboxylase (GAD), being anaerobic, will continue to convert glutamate to GABA (reaction 2) glutamate

+

GABA + COz

GAD

increasing the central GABA and therefore depressing both ventilation and blood pressure. With peripheral chemoreceptor denervation, afferent impulses do not reach the respiratory and circulatory centers. Therefore there would be no glutamate release and no increase in ventilation or blood pressure. In anesthetized mechanically ventilated, intact, and peripherally chemodenervated dogs during 1 h of 7-10s O2 breathing at normocapnia and constant minute ventilation, glutamate content of cerebral cortex and medulla increased in intact animals after 60 min of hypoxia. However, no significant changes in medullary or cerebral cortical glutamate occurred during hypoxia in dogs with denervated chemoreceptors. Thus, in the absence of peripheral chemoreceptors, hypoxia had no effect on medullary glutamate and, as has been demonstrated by others, no increase in ventilation. With severe hypoxia, particularly with peripheral chemodenervation, increased medullary GABA correlates negatively with sagittal sinus Paz; i.e., the lower the PO,, the higher the GABA (30). More importantly, with direct tracer kinetic measurement of glutamate turnover rates, in normoxia, peripheral chemodenervation reduces glutamate turnover in whole brain, which suggests a reduction in neuronal glutamatergic activity (25). These results indicate that, in the dog under hypoxic conditions, peripheral chemoreceptor stimulation causes the release of excitatory glutamate in the CNS, which may be responsible for the reported initial cardiorespiratory stimulation in response to hypoxia. With severe or more prolonged hypoxia then, the rise in brain GABA can account for the respiratory depression (44).

Future Investigations The investigations described above suggest that 1) H+ chemosensitivity and metabolism in the medulla are functionally related, possibly through ammonia and CO, fixation, to metabolism and release of amino acid

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neurotransmitters, which can have an effect on central ventilatory drive and 2) CNS metabolism and turnover rate of GABA and glutamate are altered in hypoxia and hypercapnia. Further investigations are required to examine in greater detail these mechanisms and, in particular, whether synaptic release of these amino acids is similar to whole or regional brain concentration change descri bed. The interaction of glutamate and GABA nd the rela tive i mportance of other impor Itant amino acid neurotransmitters (e.g., aspartate, glycine, taurine) in respiratory control need to be studied. Such investigations will require cooperative interdisciplinary efforts to substantiate fundamental physiological relationships be tween mechanisms of neurotransm itter reception and central regulation of respiration. This work was supported in part by National Blood Institute Grants HL-29493 and HL-29620. Address reprint requests to H. Kazemi.

Heart, Lung, and

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Glutamic acid and gamma-aminobutyric acid neurotransmitters in central control of breathing.

We review recent cross-disciplinary experimental and theoretical investigations on metabolism of the amino acid neurotransmitters glutamic acid and ga...
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