Stress and Monoamine Neurons in the Brain
Stress is a common behavioral and physiologic phenomenon that occurs in combat and other military operations and is believed to contribute to decrements in performance (Owasoyo et al., 1992). Thus, the identification of methods for counteracting stress is highly desirable. One pharmacologic countermeasure for stress currently under evaluation is the administration of an amino acid, L-tyrosine (TYR). The grounds for evaluating this amino acid follow from the fact that it is the precursor for the catecholamine neurotransmitters dopamine (DA) and norepinephrine (NE). These transmitters are found in brain neurons that are involved in the central nervous system’s response to stress; indeed, some data indicate that TYR administration can enhance DA and NE synthesis in the brain and, as a result, reverse deficient performance in both rats and humans (Banderet and Lieberman, 1989; Lehnert et al., 1984).
This chapter focuses on the biochemical basis for the assertion that TYR administration might be useful as a pharmacologic countermeasure to stress.
The conclusions are that the available evidence suggests that DA and NE synthesis in the brains of stressed individuals should respond to TYR administration by increasing neurotransmitter synthesis and release and that such alterations should affect brain functions. However, given the diversity of effects of stress on the functional states of the various DA and NE receptor subtypes, the exact responses to TYR may not always be simple. Indeed, because of the incomplete body of data regarding the effects of stress on brain catecholamine receptors, their further study in this context would appear essential to an eventual understanding of the utility of TYR and other pharmacologic agents that stimulate DA and/or NE release as stress countermeasures.
TYR administration can also influence the synthesis and release of serotonin (5-hydroxytryptamine; 5HT) in the brain, because of its role as a large neutral amino acid (LNAA). A discussion of the effects of stress on 5HT synthesis and release is thus also warranted, and can be used to evaluate whether an action of TYR on 5HT release might be a desirable consequence of TYR administration.
SYNTHESIS OF MONOAMINES IN THE BRAIN
Dopamine and Norepinephrine
The catecholamine neurotransmitters DA and NE are synthesized from the nonessential amino acid TYR. The initial step is a ring hydroxylation that is mediated by the enzyme tyrosine hydroxylase, forming dihydroxyphenylalanine (DOPA). Tyrosine hydroxylase can also hydroxylate phenylalanine to DOPA; indeed, this amino acid has been shown to be an important substrate for catecholamine biosynthesis (Karobath and Baldessarini, 1972). DOPA is converted to DA by the enzyme aromatic-L-amino acid decarboxylase (AAAD). An additional enzyme, dopamine-ß-hydroxylase, is found in neurons that synthesize and use NE as their transmitter. This enzyme mediates the beta-hydroxylation of DA to NE.
DA undergoes oxidative deamination (mediated by monoamine oxidase; MAO) to dihydroxyphenylacetic acid. A further reaction, O-methylation (mediated by catechol-O-methyltransferase; COMT), produces a second DA metabolite, homovanillic acid. The principal NE metabolite in the brain is methoxyhydroxyphenylethylglycol, which is produced in reactions mediated by MAO and COMT (Cooper et al., 1991).
The rates at which DA and NE are synthesized are controlled at the initial enzymatic step, TYR hydroxylation. Although many phenomena influence TYR hydroxylase activity, and thus DA and NE synthesis, two are especially
relevant to the present discussion. First, the activity of TYR hydroxylase is quite sensitive to neuronal activity, increasing and decreasing rapidly in parallel with the rate at which the neurons that produce DA and NE are firing (Cooper et al., 1991). Under stressful conditions, as discussed below, the firing rates of neurons that contain DA and NE increase and probably account for the observed increases in DA and NE synthesis. Second, the TYR hydroxylation rate changes rapidly in response to the TYR concentration within the neuron (Fernstrom et al., 1986). Hence, increasing brain TYR levels can stimulate DA and NE synthesis. However, TYR administration increases catecholamine synthesis only under conditions in which the neurons are active. When they are inactive, increments in the TYR level do not affect DA or NE synthesis (Fernstrom, 1990). As indicated below, stress is associated with increases in the activity of neurons that produce both DA and NE, and indeed, the synthesis of both transmitters is increased. Accordingly, in this context, the supply of additional amounts of TYR should further stimulate the production of each transmitter.
Serotonin (5-hydroxytryptamine; 5HT) is synthesized from the essential amino acid tryptophan (TRP). Like the catecholamines, the initial step in the pathway is hydroxylation, which is mediated by the enzyme tryptophan hydroxylase. The product, 5-hydroxytryptophan, is then decarboxylated to 5HT in a reaction mediated by AAAD (the same enzyme that converts DOPA to DA). Serotonin is metabolized to 5-hydroxyindoleacetic acid in a reaction initiated by MAO (Cooper et al., 1991).
Control of the 5HT synthesis rate is focused on the initial hydroxylation step. Like TYR hydroxylase, TRP hydroxylase activity is sensitive to changes in neuronal activity (Boadle-Biber et al., 1986), rising and falling with the depolarization rate. In addition, TRP hydroxylation and 5HT synthesis rates respond to the local concentration of TRP (Fernstrom, 1990). This relationship is tied to neuronal activity, however, because an increase in the brain TRP level produces a much larger stimulation of 5HT synthesis and release when the 5HT neuron is active than when it is quiescent (Fernstrom et al., 1990; Sharp et al., 1992). As discussed below, stress does not influence the activity of 5HT-producing neurons, but it does increase brain TRP levels. Hence, the increases in 5HT synthesis and turnover that occur with stress may follow from increased substrate levels.
STRESS AND BRAIN NOREPINEPHRINE
Several types of evidence suggest that stressful stimuli increase the activity of norepinephrine (NE)-producing neurons in the brain. The most direct demonstration has been provided by measurement of the firing rate of NE-producing neurons in the locus ceruleus (a nucleus in the brain stem). Levine et al. (1990) recorded the electrical activities of locus ceruleus neurons in awake, freely moving cats by means of chronically implanted electrodes. They observed that when the animals were exposed to an environmentally meaningful stress (e.g., auditory and visual, but not physical exposure to a dog or an enraged cat), the neuronal firing rate increased substantially. Biochemical methods have also revealed stress-induced increases in the firing rate of NE-producing neurons. In early studies, the turnover rate of NE in the brains of rats exposed to foot shock was estimated by prelabeling the brain NE pool with tritiated NE. The rate of loss of radioactivity was used as an index of transmitter turnover rate and neuronal activity. Using this method, Thierry et al. (1968) observed an increase in NE turnover in many regions of the rat brain (including the brain stem, cerebral cortex, and hypothalamus). A similar result was obtained by a different biochemical method, which also provided a good estimate of NE turnover: the decline in endogenous NE levels following injection of a drug that blocks NE synthesis (a-methyl-p-tyrosine). By this method, NE turnover has been found to be increased above normal rates in whole brain and in a variety of brain regions (Bliss et al., 1968; Korf et al., 1973). Finally, brain NE levels have often been observed to fall in parallel with increments in the levels of NE metabolites in stressed rats, an indication that transmitter turnover has accelerated (Nakagawa et al., 1981; Sauter et al., 1978). Indeed, in such cases, the results suggest that synthesis cannot keep up with transmitter utilization.
The influence of acute stressors has also been examined on NE receptors in the brain, primarily the ß and a2 subtypes. The most consistent finding has been that single episodes of stress do not influence ß-receptor number or affinity in the cerebral cortex or brain stem (Cohen et al., 1986; Nomura et al., 1981; Stone and Platt, 1982; U’Prichard and Kvetñanský, 1980). Inconsistent changes have been reported for the hypothalamus (Cohen et al., 1986; Stone and Platt, 1982) and other brain regions (e.g., the cerebellum and hippocampus [Nomura et al., 1981; U’Prichard and Kvetñanský, 1980]). The a2-receptor number and affinity have also been examined in a variety of rat brain regions following exposure to acute stressors and have been found to yield no simple effect. In different regions, acute stress is reported to reduce receptor number but not change affinity (hippocampus), reduce receptor number but increase
affinity (amygdala), increase receptor number but reduce affinity (midbrain), or have no affect on receptor number or affinity (hypothalamus and brain— stem) (Cohen et al., 1986; Nukima et al., 1987). For some regions, results differ across laboratories (e.g., for the cerebral cortex [Cohen et al., 1986; Nukima et al., 1987]).
On the basis of the available evidence, it appears that an appropriate conclusion for the influence of acute stress on NE receptors in the brain is that they may not be remarkably altered. As a consequence, the clear increases in NE release from nerve terminals may have sustained postsynaptic effects during a single stressful event. In such situations, where NE neurons are firing rapidly, one would certainly expect an increase in neuronal TYR levels, such as can be induced following the oral ingestion of free TYR, to stimulate NE synthesis (Lehnert et al., 1984), and thus provide a continuing source of amine for release.
Chronic stress, like single episodes of stress, is associated with increased NE synthesis and turnover (Stanford et al., 1984; Thierry et al., 1968). Such findings are consistent with the notion that NE-producing neurons are synthesizing and releasing above-normal amounts of neurotransmitter. However, unlike the acute stress context, in which NE receptors appear to show little change in their properties, some NE receptor subtypes show sizable changes with chronic stress. In particular, ß-receptor number is reported most consistently to be below normal in the cortex, brain stem, and hypothalamus (whereas the agonist affinity is normal) (Stone and Platt, 1982; Stanford et al., 1984; Torda et al., 1981, 1985). Less consistent changes have been reported for a2 receptors: increased a2 receptor populations have been reported in the hypothalamus and brain stem (Torda et al., 1981, 1985), but reduced numbers have been reported in the cerebral cortex (Lynch et al., 1983; Stanford et al., 1984). a1 receptor properties have been measured in the cortex following chronic stress and have been found to be normal (Lynch et al., 1983).
Norepinephrine receptors are coupled to second messenger systems (e.g., cyclic AMP generation and phospholipase activity), and attempts have been made to link chronic stress-induced alterations in NE receptors to effects on second messenger systems. For example, Torda et al. (1981) reported that pretreatment of rats with a drug that inhibits phospholipase activity, and ultimately cyclic AMP generation, blocks the reduction in ß-receptor number in the hypothalamus and brain stem that follows chronic stress in rats. This finding suggests that the stress-induced increase in NE release by brain neurons, via stimulation of ß-receptors on target neurons and the production
of second messenger-mediated effects, initiates events leading to ß-receptor down-regulation. As another example, Stone et al. (1985) observed that in association with the reduction in ß-receptor number in the hypothalamus and brain stem following repeated stress in rats, NE-induced cyclic AMP generation in slices from these regions incubated in vitro was also diminished. It should be noted, however, that cyclic AMP generation in response to isoproterenol, a selective ß-agonist, was not diminished in that study, suggesting that the reduction in second messenger responsiveness may not be the result of ß-receptor down-regulation. The same group of investigators (Stone et al., 1986) later reported that the diminished cyclic AMP response to NE (which stimulates all adrenergic receptors) may be mediated via a reduction in the NE effects on a-receptors.
Whatever the ultimate outcome of this line of investigation, the available evidence clearly indicates that (1) the NE receptor responsiveness changes following repeated exposure to stressful stimuli, (2) these changes are dissimilar from the effects that occur after a single exposure to stress, and (3) NE receptors and their subtypes are not affected uniformly by chronic stress, nor are the changes of a particular receptor subtype the same in different brain regions. Thus, the effects of agents that enhance NE synthesis and release (such as TYR) and that, as a result, produce particular functional effects following single stressful events, may not provide a reliable foundation for predicting functional changes under conditions of continued or repeated stress. Such effects must be sought in the context of chronic stress.
STRESS AND BRAIN DOPAMINE
Dopamine (DA) neurons are stimulated by stress. This effect has been demonstrated by using biochemical indices similar to those used to study norepinephrine (NE). Thus, stress increases the rate of decline in brain DA levels following administration of an inhibitor of DA synthesis (Thierry et al., 1976), indicating that DA turnover has increased. A similar conclusion has been drawn from results showing that stress increases the brain levels of the major DA metabolite, dihydroxyphenylacetic acid (Dunn, 1988a, Roth et al., 1988). Stress also increases the activity of tyrosine hydroxylase, measured both in vivo (Reinhard et al., 1982) and in vitro (luvone and Dunn, 1986). The direct release of DA from the neuron, as assessed by in vivo dialysis, is also stimulated by stress (Abercrombie et al., 1989). Although the results of some studies suggest that only one or two subgroups of DA-producing neurons are affected by stress (particularly those projecting to the prefrontal cortex [Roth
et al., 1988; Thierry et al., 1976]), other data indicate that essentially all DA-producing neurons in the brain can be activated by stressful stimuli (Abercrombie et al., 1989; Dunn, 1988a) (those projecting from the midbrain to the limbic system [nucleus accumbens, amygdala], the cerebral cortex, and the corpus striatum). Almost no data appear to exist regarding DA receptor responses to acute stress. In a single study, the number of D2 receptors in the prefrontal cortex and striatum were reported to be unchanged soon after a single stressful event (MacLennan et al., 1989).
From such data, it can be predicted that the administration of TYR to animals undergoing acute stress should stimulate DA synthesis and probably DA release in most brain DA-producing neurons. Functional changes might result from such biochemical effects, if the properties of DA receptors are indeed unchanged.
Relatively few data have evaluated the response of brain DA-producing neurons in animals repeatedly exposed to stressful stimuli. Available data suggest that DA-producing neurons (like NE-producing neurons) continue to be activated by repeated, stressful events. For example, Dunn (1988a) observed that daily episodes of foot shock for 10 days continued to raise dihydroxyphenylacetic acid levels in the prefrontal cortex, corpus striatum, and brain stem. Similar findings were reported by MacLennan et al. (1989).
At present, it is unclear whether DA receptor sensitivity is influenced by chronic stress. The D1 class of receptors appears largely to be unaffected (Friedhof et al., 1986; Puglisi-Allegra et al., 1991). Although changes in the D2 receptor are observed in response to chronic stress, consistent effects have not been obtained. For example, D2 receptor number is reputed by some to be increased by chronic stress in the caudate, nucleus accumbens, and prefrontal cortex (Friedhoff et al., 1986); others, however, report a reduction in D2 receptor number following restraint stress (Puglisi-Allegra et al., 1991). Some investigators have also failed to detect stress-induced changes in D2 receptors (Anderson et al., 1986) or have obtained results suggestive of a lack of effect of chronic stress on the D2 receptor (MacLennan et al., 1989).
At present, therefore, it appears that recurrent episodes of stress activate DA-producing neurons and probably lead to enhanced DA release. It also appears that the properties of DA receptors are not remarkably altered as a result. However, too few data are presently available to draw firm conclusions regarding DA receptor effects; additional work is clearly indicated. Nevertheless, the available data suggest that the administration of TYR should stimulate DA synthesis and release in animals exposed to chronic stress. As
a result, physiologic and behavioral effects may occur, taking into account the functional state of the DA receptor onto which the transmitter is released (i.e., if the DA receptor on a particular neuron is normal or up-regulated, a functional effect would be expected; if it is down-regulated, a diminished response would be anticipated).
STRESS AND BRAIN SEROTONIN
Acute stress stimulates serotonin (5-hydroxytryptamine; 5HT) synthesis and turnover in the rat brain. Acute stressors (e.g., immobilization or foot shock) rapidly increase the brain level of 5-hydroxyindoleacetic acid (5HIAA), the principal 5HT metabolite (Bliss et al., 1968; Curzon and Green, 1969). Brain 5HT levels are unaffected, suggesting that stress increases both the rate of synthesis and the rate of turnover of 5HT. Other studies support this conclusion. Morgan et al. (1975) observed that restraint stress increased the accumulation of 5HIAA in stressed rats pretreated with probenecid, a drug that blocks 5HIAA removal from the brain. Mueller et al. (1976) showed that stress increased 5HT accumulation in stressed rats pretreated with pargyline, a drug that blocks 5HT metabolism. These results provide convincing evidence that stress increases both 5HT synthesis and turnover. Similar observations have also been made in mice (Soblosky and Thurmond, 1986).
The mechanism responsible for the stress-induced increase in 5HT synthesis and turnover differs from that thought to account for the increases in dopamine (DA) and norepinephrine (NE) synthesis and turnover. First, unlike DA- and NE-producing neurons in the brain, the depolarization rate of 5HT-producing neurons is unaffected by stressful events. Using cats, Wilkinson and Jacobs (1988) observed that when animals are exposed to highly relevant environmental stressors (e.g., giving them visual and auditory but not physical exposure to an agitated dog or to an enraged cat, which causes clear sympathetic activation), the firing rate of 5HT-producing neurons is unaltered. Neuronal activation with stress therefore cannot be the source of increased transmitter synthesis in 5HT-producing neurons, as it probably is in DA- and NE-producing neurons. Second, stress elevates the brain levels of the 5HT precursor tryptophan (TRP) (Curzon et al., 1972; Dunn, 1988b), an effect that has not been observed for L-tyrosine (TYR), the precursor of DA and NE (Kennett et al., 1986). Since 5HT synthesis is known to be sensitive to small, physiologic changes in brain TRP concentrations (Fernstrom, 1990), the stress-induced rise in brain TRP levels may cause the stimulation of 5HT synthesis.
The mechanism by which stress raises brain TRP levels may center on the blood-brain barrier carrier for transporting TRP and the other large neutral amino acids (LNAAs) into the brain. Immobilization has been reported to increase the brain levels of most LNAAs (including TRP), suggesting that stress may stimulate the shared LNAA transporter (Kennett et al., 1986). This effect may derive from the stress-induced release of epinephrine into the circulation; epinephrine is known to increase brain levels of the LNAA (Eriksson and Carlsson, 1988). Further support for an LNAA transport-mediated effect of stress comes from the work of Kennett and Joseph (1981), who reported that the administration of a large dose of valine (an LNAA) blocks the stress-induced rise in brain TRP levels. Valine or TYR treatment also eliminated the stress-induced rise in neuronal 5-hydroxyindole release (Joseph and Kennett, 1983).
To summarize, the above evidence suggests that a single stressful event raises the amount of TRP taken up by the brain, possibly via the release of epinephrine into the circulation, causing brain TRP levels to rise and thus 5HT synthesis to increase. The increase in 5HT synthesis may lead to an increase in 5HT release, since stress appears to enhance 5HT-mediated brain functions (Kennett and Joseph, 1981). The administration of LNAAs, like valine or TYR, can attenuate the stress-induced increase in brain 5HT levels, with unknown consequences to brain function.
Few data with which to evaluate the effects of chronic stress on 5HT neurons appear to be available. Soblosky and Thurmond (1986) reported increases in mouse brain 5HIAA levels (with no change in 5HT) after the repeated administration of stressors for several days, suggesting that 5HT turnover (and synthesis) might be increased. However, it is unknown at present whether such changes are induced by alterations in brain TRP levels or in the activity of 5HT neurons. Chronic stress also reportedly increases postsynaptic sensitivity to 5HT, since many 5HT-mediated behaviors appear to be more responsive to 5HT agents when administered to chronically stressed rats (Kennett et al., 1985). However, the basis for this effect is presently unexplained, since in the only available report (Ohi et al., 1989), 5HT receptor kinetics have been found to be unaffected by chronic stress. These findings are not totally convincing, however, since ß-receptor properties were also found to be normal in that study. This result stands in contrast to the bulk of published data showing ß-receptor function to be increased (see above).
At present, because of the disparate nature of the small pool of available data, it is not possible to state with certainty how chronic stress affects 5HT neuronal function.
CONCLUSIONS AND RECOMMENDATIONS
Single and repeated episodes of stress cause the synthesis, turnover, and, probably, release in the brain of both dopamine (DA) and norepinephrine (NE) to increase. These effects probably derive from the stress-induced increases in the firing rate of DA- and NE-containing neurons. Under such conditions, in which DA and NE utilization is substantially increased, the administration of tyrosine should stimulate DA and NE synthesis and probably release.
With acute stress, no clear changes in the properties of NE receptors are apparent, although data are often conflicting. Almost no data regarding the effects of acute stress on DA receptors appear to be available. With chronic stress, ß-adrenergic receptors are down-regulated, suggesting that postsynaptic responses in brain circuits employing ß-receptors may be attenuated (although the functional effects of such changes do not appear to have been evaluated). a1-Adrenergic receptors are unaffected by chronic stress, but both increases and decreases have been reported for a2-receptor numbers in different brain regions. For DA receptors, chronic stress does not appear to change D1 receptors; data on the D2 receptor are few and conflicting. It is thus difficult to conclude with any confidence whether and how D2 receptors change following repeated stress.
Overall, given this diversity of catecholamine receptor responses to chronic stress and the relatively small number of studies that have defined them, it is presently impossible to conclude how brain circuits with catecholamine-producing neurons and postsynaptic receptors should respond to repeated stressful events. Additional studies should be encouraged, to define with more certainty the effects of stress on catecholamine receptors in particular brain regions and then to attempt to correlate such changes with functions specific to the affected regions. Without such information, the pharmacologic development and application of agents like L-tyrosine (TYR) or drugs that selectively target particular catecholamine receptors cannot be attempted with any hope of obtaining highly selective and useful effects on performance.
Single episodes of stress cause the synthesis, turnover, and possibly release ofserotonin (5-hydroxytryptamine; 5HT) in the brain to increase. These effects do not derive from stress-induced increases in the firing rate of 5HT neurons but, rather, derive from increases in brain tryptophan (TRP) levels,
possibly induced by an effect of stress on the transport of TRP into the brain. Under such conditions, in which the increase in 5HT synthesis is probably dependent on an increased supply of TRP to the brain, the administration of TYR to stimulate catecholamine production could block the stress-related increase in 5HT synthesis (by antagonizing TRP transport into the brain). The impact of such an effect on performance is unknown, but clearly, it should be examined. Potential effects could be imagined on sleep and sensitivity to painful and other environmental stimuli, phenomena that have previously been connected to 5HT neuronal function.
Finally, too few data are presently available to conclude how repeated or chronic stress influences 5HT synthesis and release. Additional information is therefore required before any notion can be formulated regarding how the administration of TYR might have an impact on serotonergic function under conditions of repeated stress.
Overall, given the impact of stress on performance, and on health in general, it is surprising that the influence of stress on the monoamine-producing neurons in the brain (probably the most examined group of transmitter-specific neurons in the past quarter century) is so incompletely studied or understood. A greater body of fundamental information on this relationship should be collected to better approach the applied question of how amino acids and drugs can be utilized effectively to combat the decrements in performance that accompany stress.
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CHANDON PRASAD: I would like to make a comment with regard to receptor binding, particularly dopamine receptor binding. When one looks at the earlier binding studies, and even the new ones, one must be very careful in interpreting their results.
JOHN FERNSTROM: I agree with you 100 percent. Most investigators worry to some extent about that problem. I think your point is well taken. I think the conclusion would be that more studies are needed in this area; they are not there now.
GEORGE BRAY: At the end of each of your sections, you state what tyrosine might do to monoamine synthsis and receptors. Does that tell us that we are going to hear about tyrosine later or that no one has done the experiments?
JOHN FERNSTROM: I was originally thinking, when I was invited to give this talk, that I would be responsible for that. But then when the workshop program was finally sent to me, I saw that there were several people who investigate tyrosine effects on the list of participants. So I assumed they would be discussing this information, and did not spend much time myself dealing with it.
RICHARD WURTMAN: I think you set it up beautifully, too. There were several people in my laboratory who did some studies on the effect of giving tyrosine to stress-immobilized animals. They found that the stress per se depleted hypothalamic locus ceruleus. Norepinephrine modified behavior; that is, there was less spontaneous activity, less poking their nose in the hole in the ground, which I guess means something to a rat (I am not sure what). But also, of course, stress caused striatocortical activation of corticosterone release. Then they found that giving tyrosine blocked all of these effects.
I have been waiting to see some other laboratories confirm or not confirm—I would hope confirm—these findings because they are from our lab, and I believe them; but if they are really powerful, it means that physicians might have an available strategy for diminishing cortisone responses, for example, in somebody who has broken their leg and has diabetes.
I am not aware of any studies. Do you know of any other studies?
JOHN FERNSTROM: No. In fact, your study with Lehnert was more interesting than you have stated, because tyrosine was put in the diet. So the animals were actually eating increased amounts of tyrosine supplied chronically in their diets. Then an acute stress was provided, and the effect of the tyrosine was to prevent the stress-induced depletion of brain NE. It would be very interesting to do a chronic stress study, too, to see if tyrosine supplementation would continue to be beneficial.