Introduction: Norepinephrine as an ‘umbrella’ neuromodulators

WILLIAM Z. POTTER. M.D.• Ph.D.

Introduction: Norepinephrine

as an 'umbrella' neuromodulator In addition to their established role in treating depression. the drugs classified as antidepressants are coming to be used for a variety of other problems. Their use in several diverse syndromes will be described in this supplement: panic-anxiety with or without phobia. anorexia nervosa. bulimia. cocaine withdrawal. attention deficit disorder. and obsessivecompulsive disorder. This variety of uses raises the question of whether there is any way in which we can conceptualize an underlying mechanism to explain the effects of so-called antidepressants on so many different syndromes. The common theme. of course. is that antidepressants have certain biochemical effects that can be measured. We must therefore consider a general model of a synapse (Figure 1). Following electrical impulse or some other form of stimulation. transmitter is released and then impinges upon different types of post-synaptic receptors. which themselves will have their own degree of receptivity to this transmitter. These receptors then communicate by means of secondary messengers within the receptor cell. which are tied ultimately to one or another physiologic effect. In the three major neurotransmitter systems. uptake mechanisms are critical for deactivation. Thus. with dopamine. serotonin. and norepinephrine. it is the uptake mechanism that deactivates the neurotransmitter. There are also presynaptic receptors that can themselves be stimulated. have their own degree of sensitivity. and regulate neurotransmitter release. allowing for multiple and quite complicated sites of drug action. And of course there are metabolic pathways inside the neuronal ending. which can break down neurotransmitters into a series of metabolites; mono-

NOVEMBER 1986· VOL 27· NO II (SUPPLEMENT)

amine oxidase (MAO) is one of the chief enzymes responsible for neurotransmitter metabolism. Most studies of neurotransmitter function over the years have tended to look at what might be happening to the intensity of the stimulus. working on the assumption that this is related to the amount of neurotransmitter in the synapse. MQre recently. there has been a good deal of attention paid to receptivity. that is. the state ofthe various pre- and postsynaptic receptors shown in Figure 2. Obviously. some sort of combination. in these interacting systems. between the amount of stimulus and the receptivity of the system will produce a physiologic effect. Ultimately. it is such an effect that we are interested in; this is a very important theme which we will come back to. because it is central to the unitary notion we are looking for that may allow us to tie together some of the varied uses of antidepressants.

Chronic biochemical effects of antidepressants Except for attention deficit disorder. the syndromes to be discussed depend on chronic treatment to evaluate response. If we look at the chronic biochemical effect of antidepressants (Table I). we see immediately that the tricyc1ics are particularly potent in terms of inhibiting either norepinephrine or serotonin uptake. MAO inhibitors do not seem to work that way. Rather. under chronic conditions they have the net effect of increasing norepinephrine release. Blocking MAO increases the amount of neurotransmitter being stored. so that when there is a stimulus more is released. Since their primary effect is to block MAO, these drugs will have consequent effects on any of the neurotransmitters that are dependent on that en-

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Introduction

Axon termination

Synapse

Next neuron, gland, muscle, etc.

Ea,b,c...

____ C-AMP

~E1,2,3 ...

M-T

FIGURE I-General modelfor synapse. T=neurotransmitter; M-T=metabolite of transmitter; MAO=monoamine oxidase; /-=inhibition of release; P/P=phosphatidyl inositol biphosphate; C-AMP=cyclic AMP; E=any ofa series ofeffects.

Postsynaptic

Presynaptic

a, Ea,b,c...

____ C-AMP

~E1,2,3 ...

M-T

FIGURE 2-Model of norepinephrine synapse in central nervous system. T=norepinephrine; M-T=MHPG;
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PSYCHOSOMATICS

Table 1-Tricyclic Antidepressants and MAOls: Chronic Biochemical Effects

In Animals TCAs

MAOI

lU l l-lH

0

tt

SHTrelease

?

o-t

MAO activity

l

Hl

NE uptake inhibition NE release SHT uptake inhibition

0

zyme. This does not give us a great deal of specificity, since MAO acts on all three major neurotransmitters-norepinephrine, serotonin, and dopamine-while the tricyclics seem to affect only the first two (Table 2), and through a different mechanism. Our efforts to understand antidepressant effects, therefore, generally focus on the serotonin and norepinephrine systems. We attempt to measure the effect of antidepressants on the serotonin system in man by looking at such things as prolactin response to infusions of a precursor (L-tryptophan) or to thyrotropin-releasing honnone, or at cortisol response to 5-hydroxytryptophan, another precursor of serotonin. Thus far, results have been very inconclusive. Until we come up with better measures of serotonin, we will not be able to say much about the functional consequence ofthese serotonergic changes in man. We will therefore concentrate on those measures that are related to norepinephrine efficiency.

We can measure several aspects of the norepinephrine system. These include (I) basal output (ie, the amount of norepinephrine in the synapse, or that which spills out of the synapse); (2) norepinephrine response to either physiologic challenge, such as moving from a lying to a standing position, or behavioral challenge, such as exposure to a panicinducing situation; (3) response to direct and indirect norepinephrine agonists or antagonists; and (4) characteristics of norepinephrine receptors on platelets or lymphocytes. In order to understand such measures, we must identify several targets for alteration on a noradrenergic neuron. As shown in Figure 2, such targets include both presynaptic sites like the (X2 inhibitory receptors (there are also important (X2 postsynaptic receptors, not shown), the primary neurotransmitter (T) uptake site, and an associated regulatory one (?'H-DMI). Postsynaptic targets include (x, receptors, which are linked to phosphatidyl inositol biphosphate, a second messenger with effects on calcium ions, which can evoke muscle contraction or stimulation of specific enzymes, and 13, receptors, which are linked to cyclic AMP and the cascades that its stimulation initiates. These "targets" can all be measured, directly in animal studies and indirectly in human studies, and are shown to be altered both by tricyclics and monoamine oxidase inhibitors, but not always in the same way. From such findings, we get certain clues about how different classes of antidepressants work. (continued)

Table 2-Putatlve Effects of Trlcycllcs and MAOls on Neurotransmitters and/or Their Metabolites (Human Studies)

Norepinephrine system One of the major roles of norepinephrine in the central nervous system is as a modulator of incoming signals. It increases the signal-to-noise ratio of incoming messages. A nerve cell at rest tends to fire spontaneously, producing background "noise." Norepinephrine seems to serve a focusing function for other neurotransmitter systems, by suppressing that spontaneous, noisy, nonfunctional firing, so that the subsequent firing of a neuron becomes highly targeted to function, and incoming signals become recognized better by that neuron. Any drugs that have a major effect on the noradrenergic system, therefore, are likely to have a multitude of subsequent effects on several systems. This, we believe, may provide the rationale for the usefulness of antidepressants in a variety of syndromes.

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TCAs

MAOls

H H

JH JH

Norepinephrine (HE) MHPG in urine or CSF "Sum" of metabolites in urine

serotonin (5HY) SHT via S-HIAA" in CSF

H

Dopamine (DA) DA via HVAt in CSF

0

J-B

• 5-hydroxylndoleacetlc aCid (the major melabollte of serotonin In the cerebrospinal fluid (CSF» Homovanlilic aCid (the majOr metabolite of dopamine In Ihe CSF)

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Introduction

Table 4-Chronic Effects of Trlcyclics and MAOls on Receptor Density or Coupling to Cyclic AMP in Animals Receptor ~-adrenergic

u, OI:?

TeAs

H

H

o-t o-H

0

5-HT ,

0

5-HT?

~-H

GABA-B

MAOls

tt

H H H

o-t

To review, the primary effect of tricyclic antidepressants is to decrease the removal or ..clearance" of the neurotransmitter from the synaptic cleft by reuptake inhibition. With the MAO inhibitors, of course, one obtains this result by blocking MAO. Interestingly, with long-term tricyclic use, levels of norepinephrine in the blood stream increase, whereas with MAO inhibitors they decrease (Table 3). We believe the reason for this disparity is that the blockade of clearance by the tricyclics is so significant that in the peripheral sympathetic nervous system this effect overwhelms any other (in this case, the concomitant effect of reducing the total metabolism and output of norepinephrine). Under the influence of both classes of antidepressants, the total output of norepinephrine and all of its metabolites actually goes

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down, as measured by urine or CSF levels of MHPG or by the sum of norepinephrine's metabolites in urine (Table 2). This finding is very important, because it indicates that the neurotransmitter system is required to produce less norepinephrine when these drugs are present.

Increased noradrenergic efficiency In terms of chronic effects on neuroreceptors, Table 4 shows that, at least in animal studies, ~-adrenergic receptors are consistently affected by both classes of drugs, being substantially reduced either in number or responsivity to stimulation; the 5HT) subtype of serotonin receptors is also reduced in number. Very recently it has been reported that GABA-B receptors may also be affected by antidepressants. Since these receptors appear to be involved in anxiety, this finding may tum out to be important to the understanding of the chronic antianxiety effects of the tricyclics and MAO inhibitors. Thus, we see that giving antidepressants chronically decreases neurotransmitter output as well as decreasing the number of postsynaptic receptors; by this analysis, both total stimulus and receptivity would seem to be lowered. Yet, when we look at a variety of measures related to neurotransmitter function (Table 5), we find, for instance, that the plasma norepinephrine response to movement from a lying to a standing position is actually augmented by the tricyc1ies, and is not affected by the MAOIs despite reductions in resting norepinephrine. Heart rate response is also either augmented or maintained (under certain conditions,

PSYCHOSOMATICS

which norepinephrine has a strong modulatory role. Since norepinephrine neurons project to so many areas of the brain, this model allows for a very wide range of candidate systems that may be dysregulated in specific psychiatric syndromes.

Table 6-Pathways and Results of Increasing Norepinephrine System Efficiency by Chronic Antidepressant Administration

I

Pathweye • Down-regulated preceptors • Reduced whole-body turnover of NE • NE output(s) sustained or increased

Results • NE focusing of multiple inputs less demanding • Restabilization of dysregulated system

-

-

MAOIs can lower the heart rate, but this does not necessarily occur at doses that produce substantial biochemical changes). Similarly, average daily melatonin output, which is very much under noradrenergic control (norepinephrine drive), is either maintained or, as shown in the most recent studies, actually increased. These drugs, then, have the remarkable effect of reducing neurotransmitter output and reducing neurotransmitter receptivity, while the important physiologic effects that we can measure are actually sustained or increased. We can therefore say that the efficiency of the noradrenergic system has been increased throughout the body (Table 6). To put a more elaborate interpretation on this, I would suggest that the burden on norepinephrine of focusing multiple inputsincreasing the signal-to-noise ratio of relevant physiologic inputs-becomes less demanding, and this permits restabilization of either a dysregulated norepinephrine system, which we see in depression, or of other dysregulated neural systems (including those using peptides as modulators), in

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"Umbrella" modulating effect of norepinephrine system The norepinephrine and serotonin systems influence each other, and it becomes impossible under chronic conditions to alter one without altering the other, so it is also very important to elucidate the changes in the serotonin system in patients receiving antidepressants. Such changes may tum out to be important for some of the syndromes discussed in this supplement. The norepinephrine system can also interact in multiple ways with the dopamine system. The dopamine system is influenced directly by the serotonin system. This influence, however, is relatively unidirectional; emerging data suggest that serotonergic regulation has important input on dopaminergic regulation but not vice versa, at least not directly. In conclusion, I would emphasize these complex interactiol1$, in which the norepinephrine system plays the role of a modulatory umbrella, with itself strongly influenced by the serotonin system but not by the dopamine system. Thus, our ability to increase the efficiency of the norepinephrine system can have widespread consequences and help us to understand why so many different syndromes can be affected by these two very chemically potent classes of drugs. We can now demonstrate in man that antidepressants have striking biochemical effects, which can fundamentally be understood as a change in the efficiency of one of the major regulatory systems-the central norepinephrine one. As you read the papers that follow, you may use this general overview as a background for considering that the drugs called antidepressants might in fact have a wide range of therapeutic effects in discretely different syndromes. 0

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