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Neurotransmitters and circuits in mood disorders

Neurotransmitters and circuits in mood disorders

Three principal neurotransmitters have long been implicated in both the pathophysiology and treatment of mood disorders. They are norepinephrine, dopamine, and serotonin, and comprise what is sometimes called

Figure 6-20. . Another subcategory within the bipolar spectrum may be “bipolarity in the setting ofBipolar VI dementia,” termed bipolar VI. Mood instability here begins late in life, followed by impaired attention, irritability, reduced drive, and disrupted sleep. The presentation may initially appear to be attributable to dementia or be considered unipolar depression, but it is likely to be exacerbated by antidepressants and may respond to mood stabilizers.

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Figure 6-21. . In recent years there has been a paradigm shift in terms of thePrevalence of mood disorders recognition and diagnosis of patients with mood disorders. That is, many patients once considered to have major depressive disorder (old paradigm, left) are now recognized as having bipolar II disorder or another form of bipolar illness within the bipolar spectrum (shifting paradigm, right).

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Table 6-2 Is it unipolar or bipolar depression? Questions to ask

the monoamine neurotransmitter system. These three monoamines often work in concert. Many of the symptoms of mood disorders are hypothesized to involve dysfunction of various combinations of these three systems. Essentially all known treatments for mood disorders act upon one or more of these three systems.

We have extensively discussed the dopamine system in and illustrated it in Chapter 4 Figures 4-5 through . We have extensively discussed the serotonin system in and illustrated it in 4-11 Chapter 5

, , , and . Here we introduce the reader to the norepinephrine system, andFigures 5-13 5-14 5-25 5-27 also show some interactions among these three monoaminergic neurotransmitter systems.

Noradrenergic neurons

The noradrenergic neuron utilizes norepinephrine (noradrenaline) as its neurotransmitter. Norepinephrine (NE) is synthesized, or produced, from the precursor

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Figure 6-22. . Although all symptoms of a major depressive episode can occurBipolar depression symptoms in either unipolar or bipolar depression, some symptoms may present more often in bipolar versus unipolar depression, providing hints if not diagnostic certainty that the patient has a bipolar spectrum disorder. These symptoms include increased time sleeping, overeating, comorbid anxiety, psychomotor retardation, mood lability during episodes, psychotic symptoms, and suicidal thoughts.

Figure 6-23. A currently unanswered question is whether moodIs major depressive disorder progressive? disorders are progressive. Does undertreatment of unipolar depression, in which residual symptoms persist and relapses occur, lead to progressive worsening of illness, such as more frequent recurrences and poor inter-episode recovery? And can this ultimately progress to a bipolar spectrum condition and finally treatment resistance?

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Figure 6-24. There is some concern that undertreatment of discrete manicIs bipolar disorder progressive? and depressive episodes may progress to mixed and dysphoric episodes and finally to rapid cycling and treatment resistance.

Figure 6-25. . Tyrosine (TYR) a precursor to norepinephrine (NE), is taken up intoNorepinephrine is produced NE nerve terminals via a tyrosine transporter and converted into DOPA by the enzyme tyrosine hydroxylase (TOH). DOPA is then converted into dopamine (DA) by the enzyme DOPA decarboxylase (DDC). Finally, DA is converted into NE by dopamine -hydroxylase (DBH). After synthesis, NE is packaged into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored there until its release into the synapse during neurotransmission.

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amino acid tyrosine, which is transported into the nervous system from the blood by means of an active transport pump ( ). Once inside the neuron, the tyrosine is acted upon by threeFigure 6-25 enzymes in sequence. First, tyrosine hydroxylase (TOH), the rate-limiting and most important enzyme in the regulation of NE synthesis. Tyrosine hydroxylase converts the amino acid tyrosine into DOPA. The second enzyme then acts, namely, DOPA decarboxylase (DDC), which converts DOPA into dopamine (DA). DA itself is a neurotransmitter in dopamine neurons, as discussed in Chapter 4 and illustrated in . However, for NE neurons, DA is just a precursor of NE. In fact the thirdFigure 4-5 and final NE synthetic enzyme, dopamine -hydroxylase (DBH), converts DA into NE. NE is then stored in synaptic packages called vesicles until released by a nerve impulse ( ).Figure 6-25

NE action is terminated by two principal destructive or catabolic enzymes that turn NE into inactive metabolites. The first is monoamine oxidase (MAO) A or B, which is located in mitochondria in the presynaptic neuron and elsewhere ( ). The second is catechol- -methyl-transferaseFigure 6-26 O (COMT), which is thought to be located largely outside of the presynaptic nerve terminal (Figure 6-26 ).

The action of NE can be terminated not only by enzymes that destroy NE, but also by a transport pump for NE that removes NE from acting in the synapse without destroying it ( ). In fact,Figure 6-27 such inactivated NE can be restored for reuse in a later

Figure 6-26. . Norepinephrine’s action can be terminated throughNorepinephrine’s action is terminated multiple mechanisms. Dopamine can be transported out of the synaptic cleft and back into the presynaptic neuron via the norepinephrine transporter (NET), where it may be repackaged for future use. Alternatively, norepinephrine may be broken down extracellularly via the enzyme catechol- -methyl-transferase (COMT).O Other enzymes that break down norepinephrine are monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), which are present in mitochondria both within the presynaptic neuron and in other cells, including neurons and glia.

neurotransmitting nerve impulse. The transport pump that terminates synaptic action of NE is sometimes called the “NE transporter” or NET and sometimes the “NE reuptake pump.” This NE reuptake pump is located on the presynaptic noradrenergic nerve terminal as part of the presynaptic machinery of the neuron, where it acts as a vacuum cleaner whisking NE out of the synapse, off the

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synaptic receptors, and stopping its synaptic actions. Once inside the presynaptic nerve terminal, NE can either be stored again for subsequent reuse when another nerve impulse arrives, or destroyed by NE-destroying enzymes ( ).Figure 6-26

The noradrenergic neuron is regulated by a multiplicity of receptors for NE ( ). TheFigure 6-27 norepinephrine transporter or NET is one type of receptor, as is the vesicular monoamine transporter (VMAT2) that transports NE in the cytoplasm of the presynaptic neuron into storage vesicles (Figure

). NE receptors are classified as or , , or , or as , , or . All can be postsynaptic, but6-27 1 2A 2B 2C 1 2 3 only receptors can act as presynaptic autoreceptors ( through ). Postsynaptic2 Figures 6-27 6-29

receptors convert their occupancy by norepinephrine at , , , , , , or receptors into1 2A 2B 2C 1 2 3 physiological functions, and ultimately into

Figure 6-27. . Shown here are receptors for norepinephrine that regulate itsNorepinephrine receptors neurotransmission. The norepinephrine transporter (NET) exists presynaptically and is responsible for clearing excess norepinephrine out of the synapse. The vesicular monoamine transporter (VMAT2) takes norepinephrine up into synaptic vesicles and stores it for future neurotransmission. There is also a presynaptic autoreceptor,2 which regulates release of norepinephrine from the presynaptic neuron. In addition, there are several postsynaptic receptors. These include , , , , , , and receptors.1 2A 2B 2C 1 2 3

changes in signal transduction and gene expression in the postsynaptic neuron ( ).Figure 6-27

Presynaptic receptors regulate norepinephrine release, so they are called (2 autoreceptors Figures

and ). Presynaptic autoreceptors are located both on the axon terminal (i.e., terminal 6-27 6-28 2 2 receptors: and ) and at cell body (soma) and nearby dendrities; thus, these latter Figures 6-27 6-28 2 presynapic receptors are called receptors ( ). Presynaptic receptorssomatodendritic 2 Figure 6-29 2 are important because both the terminal and the somatodendritic receptors are autoreceptors. That2 is, when presynaptic receptors recognize NE, they turn off further release of NE ( and 2 Figures 6-27

). Thus, presynaptic autoreceptors act as a brake for the NE neuron, and also cause what is6-28 2 known as a negative-feedback regulatory signal. Stimulating this receptor (i.e., stepping on the brake) stops the neuron from firing. This probably occurs physiologically to prevent over-firing of the

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NE neuron, since it can shut itself off once the firing rate gets too high and the autoreceptor becomes stimulated. It is worthy to note that drugs can not only mimic the natural functioning of the NE neuron by stimulating the presynaptic neuron, but drugs that antagonize this2

Figure 6-28. . Shown here are presynaptic -adrenergic autoreceptorsAlpha-2 receptors on axon terminal 2 located on the axon terminal of the norepinephrine neuron. These autoreceptors are “gatekeepers” for norepinephrine. That is, when they are not bound by norepinephrine, they are open, allowing norepinephrine release (A). However, when norepinephrine binds to the gatekeeping receptors, they close the molecular gate and prevent norepinephrine from being released (B).

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Figure 6-29. . Presynaptic -adrenergic autoreceptors are also located in theSomatodendritic receptors2 2 somatodendritic area of the norepinephrine neuron, as shown here. When norepinephrine binds to these 2 receptors, it shuts off neuronal impulse flow in the norepinephrine neuron (see loss of lightning bolts in the neuron in the lower figure), and this stops further norepinephrine release.

same receptor will have the effect of cutting the brake cable, thus enhancing release of NE.

Monoamine interactions: NE regulation of 5HT release

Norepinephrine clearly regulates norepinephrine neurons via receptors ( and ); in 2 Figures 6-28 6-29

, we showed that dopamine regulates dopamine neurons via D receptors (Chapter 4 2 Figures 4-8

through ); and in we showed that serotonin regulates serotonin neurons via 5HT4-10 Chapter 5 1A and 5HT presynaptic receptors ( and ) and via 5HT receptors (illustrated in 1B/D Figures 5-25 5-27 3

) and 5HT postsynaptic receptors ( through ). Obviously, the threeChapter 7 7 Figures 5-60A 5-60C

monoamines are all able to regulate their own release.

There are also numerous ways in which these three monoamines interact to regulate each other. For example, in we showed that serotonin regulates dopamine release via 5HT receptors (Chapter 5 1A

and ), 5HT receptors ( , , ) and 5HT receptors (Figures 5-15C 5-16C 2A Figures 5-15A 5-16A 5-17 2C ); we also showed that serotonin regulates norepinephrine release via 5HT receptorsFigure 5-52A 2C

( ) and mentioned that serotonin regulates dopamine and norepinephrine via 5HTFigure 5-52A 3 receptors, which is illustrated in on antidepressants.Chapter 7

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We now show that NE reciprocally regulates 5HT neurons via both and receptors (1 2 Figures 6-30A

through ): receptors are the accelerator ( ), and receptors the brake (6-30C 1 Figure 6-30B 2 Figure

) on 5HT release. That is, NE neurons from the locus coeruleus travel a short distance to the6-30C midbrain raphe ( , box 2) and there they release NE onto postsynaptic receptors onFigure 6-30B 1 5HT neuronal cell bodies. That directly stimulates 5HT neurons and acts as an accelerator for 5HT release, causing release of 5HT from their downstream axons ( , box 1). NorepinephrineFigure 6-30B neurons also innervate the axon terminals of 5HT neurons ( ). Here NE is releasedFigure 6-30C directly onto postsynaptic receptors that inhibit 5HT neurons, acting as a brake on 5HT, thus2 inhibiting 5HT release ( , box 1). Which action of NE predominates will depend uponFigure 6-30C which end of the 5HT neuron receives more noradrenergic input at any given time.

There are many brain areas where 5HT, NE, and DA projections overlap, creating opportunities for monoamine interactions throughout the brain and at many different receptor subtypes (Figures 6-31 through ). Numerous known inter-regulatory pathways and receptor interactions exist among the6-33 three monoaminergic neurotransmitter systems in order for them to influence each other and change the release not only of their own neurotransmitters, but also of other monoamines.

The monoamine hypothesis of depression

The classic theory about the biological etiology of depression hypothesizes that depression is due to a deficiency of monoamine neurotransmitters. Mania may be the opposite, due to an excess of monoamine neurotransmitters. At first, there was a great argument about whether norepinephrine (NE) or serotonin (5-hydroxytryptamine, 5HT) was the more important deficiency, and dopamine was relatively neglected. Now the monoamine theory suggests that the entire monoaminergic neurotransmitter system of all three monoamines NE, 5HT, and DA may be malfunctioning in various brain circuits, with different neurotransmitters involved depending upon the symptom profile of the patient.

The original conceptualization was rather simplistic and based upon observations that certain drugs that depleted these neurotransmitters could induce depression, and that all effective antidepressants act by boosting one or more of these three monoamine neurotransmitters. Thus, the idea was that the “normal” amount of monoamine neurotransmitters ( ) somehow became depleted,Figure 6-34A perhaps by an unknown disease process, by stress, or by drugs ( ), leading to theFigure 6-34B symptoms of depression.

Direct evidence for the monoamine hypothesis is still largely lacking. A good deal of effort was expended especially in the 1960s and 1970s to identify the theoretically predicted deficiencies of the monoamine neurotransmitters in depression and an excess in mania. This effort to date has unfortunately yielded mixed and sometimes confusing results, causing a search for better explanations of the potential link between monoamines and mood disorders.

The monoamine receptor hypothesis and gene expression

Because of these and other difficulties with the monoamine hypothesis, the focus of hypotheses for the etiology of mood disorders has shifted from the monoamine neurotransmitters themselves to their receptors

Figure 6-30

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A. . Norepinephrine regulatesAlpha receptors mediate norepinephrine regulation of serotonin release serotonin release. It does this by acting as a brake on serotonin release at cortical receptors on axon terminals2 (1) and as an accelerator of serotonin release at receptors at the somatodendritic area (2).1

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B. . Alpha-1-adrenergic receptors are located in theRaphe receptors stimulate serotonin release1 somatodendritic regions of serotonin neurons. When these receptors are unoccupied by norepinephrine, some serotonin is released from the serotonin neuron. However, when norepinephrine binds to the receptor (2), this1 stimulates the serotonin neuron, accelerating release of serotonin (1).

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C. . Alpha-2-adrenergic heteroreceptors are located on the axonCortical receptors inhibit serotonin release2 terminals of serotonin neurons. When norepinephrine binds to the receptor this prevents serotonin from being2 released (1).

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Figure 6-31. . Dopamine has widespread ascending projections that originateMajor dopamine projections predominantly in the brainstem (particularly the ventral tegmental area and substantia nigra) and extend via the hypothalamus to the prefrontal cortex, basal forebrain, striatum, nucleus accumbens, and other regions. Dopaminergic neurotransmission is associated with movement, pleasure and reward, cognition, psychosis, and other functions. In addition, there are direct projections from other sites to the thalamus, creating the “thalamic dopamine system,” which may be involved in arousal and sleep. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

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Figure 6-32. . Norepinephrine has both ascending and descendingMajor norepinephrine projections projections. Ascending noradrenergic projections originate mainly in the locus coeruleus of the brainstem; they extend to multiple brain regions, as shown here, and regulate mood, arousal, cognition, and other functions. Descending noradrenergic projections extend down the spinal cord and regulate pain pathways. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

Figure 6-33. . Like norepinephrine, serotonin has both ascending and descendingMajor serotonin projections projections. Ascending serotonergic projections originate in the brainstem and extend to many of the same regions as noradrenergic projections, with additional projections to the striatum and nucleus accumbens. These ascending projections may regulate mood, anxiety, sleep, and other functions. Descending serotonergic projections extend down the brainstem and through the spinal cord; they may regulate pain. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

and the downstream molecular events that these receptors trigger, including the regulation of gene expression and the role of growth factors. There is also great interest in the influence of nature and nurture on brain circuits regulated by monoamines, especially what happens when epigenetic changes from stressful life experiences are combined with the inheritance of various risk genes that can make an individual vulnerable to those environmental stressors.

The neurotransmitter receptor hypothesis of depression posits that an abnormality in the receptors for monoamine neurotransmitters leads to depression ( ). Thus, if depletion of monoamineFigure 6-35 neurotransmitters is the central theme of the monoamine hypothesis of depression ( ),Figure 6-34B the neurotransmitter receptor hypothesis of depression takes this theme one step further: namely, that the depletion of neurotransmitter causes compensatory upregulation of postsynaptic neurotransmitter receptors ( ). Direct evidence for this hypothesis is also generally lacking.Figure 6-35 Postmortem studies do consistently show increased numbers of serotonin 2 receptors in the frontal cortex of patients who commit suicide. Also, some neuroimaging studies have identified abnormalities in serotonin receptors of depressed patients, but this approach has not yet been successful in identifying consistent and replicable molecular lesions in receptors

Figure 6-34

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A. . According to the classic monoamine hypothesis ofClassic monoamine hypothesis of depression, part 1 depression, when there is a “normal” amount of monoamine neurotransmitter activity, there is no depression present.

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B. . The monoamine hypothesis of depression positsClassic monoamine hypothesis of depression, part 2 that if the “normal” amount of monoamine neurotransmitter activity becomes reduced, depleted, or dysfunctional for some reason, depression may ensue.

for monoamines in depression. Thus, there is no clear and convincing evidence that monoamine deficiency accounts for depression – i.e., there is no “real” monoamine deficit. Likewise, there is no clear and convincing evidence that abnormalities in monoamine receptors account for depression. Although the monoamine hypothesis is obviously an overly simplified notion about mood disorders, it has been very valuable in

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Figure 6-35. . The monoamine receptor hypothesis ofMonoamine receptor hypothesis of depression depression extends the classic monoamine hypothesis of depression, positing that deficient activity of monoamine neurotransmitters causes upregulation of postsynaptic monoamine neurotransmitter receptors, and that this leads to depression.

focusing attention upon the three monoamine neurotransmitter systems norepinephrine, dopamine, and serotonin. This has led to a much better understanding of the physiological functioning of these three neurotransmitters, and especially the various mechanisms by which all known antidepressants act to boost neurotransmission at one or more of these three monoamine neurotransmitter systems, and how certain mood-stabilizing drugs may also act on the monoamines. Research is now turning to the possibility that in depression there may be a deficiency in downstream signal transduction of the monoamine neurotransmitter and its postsynaptic neuron that is occurring in the presence of normal amounts of neurotransmitter and receptor. Thus, the hypothesized molecular problem in depression could lie within the molecular events distal to the receptor, in the signal transduction cascade system, and in appropriate gene expression ( ). Different molecular problems may account forFigure 6-36 mania and bipolar disorder.

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