Chapter 4 Chemical Neuroanatomy of the Primate Brain

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Darlene S. Melchitzky, David A. Lewis: Chapter 4. Chemical Neuroanatomy of the Primate Brain, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by

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Chapter 4. Chemical Neuroanatomy of the Primate Brain

CHEMICAL NEUROANATOMY OF THE PRIMATE BRAIN: INTRODUCTION

Other chapters in this textbook address the questions of how psychotropic medications affect the brain to reduce the severity of the clinical features and

symptoms of psychiatric disorders and to produce the side effects that frequently accompany their administration. Appropriately, much attention has been

directed toward the neurotransmitter systems that are the targets of these medications. A potential consequence of this emphasis is the idea, in its simplest

form, that an excess or deficit in the functional activity of a given neurotransmitter is the pathophysiological basis for the clinical features of interest.

Although variants of this view have been very useful in motivating investigations of the molecular underpinnings and biochemical features of

neurotransmitter systems and in spurring the development of novel psychopharmacological agents that influence these systems, in the extreme case this

perspective tends to consider a given psychiatric disorder as the consequence solely of the postulated disturbance in a neurotransmitter system.

In addition to this limited conceptual perspective, neurotransmitter-based views of psychiatric disorders sometimes seem to attribute behavioral, emotional,

or cognitive functions to neurotransmitters instead of explicitly recognizing that neurotransmitters have defined actions on receptors, whereas behaviors,

emotions, and cognitive abilities represent emergent properties of the integrated activity of large networks of neurons. This view of psychiatric disorders was

influenced, at least in part, by extrapolations from earlier successes in the study of Parkinson’s disease, which was then viewed as a single-neurotransmitter

(i.e., dopamine) disease resulting from a localized neuropathology (e.g., cell death in the substantia nigra).

In recent years, however, greater attention has been given to neural circuitry–based views of psychiatric disorders that reflect a fuller appreciation of the fact

that neurotransmitters act in an anatomically constrained fashion to produce specific biochemical effects at the cellular level and that the localization of

function(s) is a consequence of the flow of information processing through the neural circuits formed by neurotransmitter systems (Lewis 2002).

Consequently, the goal of this chapter is to provide a brief overview of the major neurotransmitter systems of the primate brain, with reference to the rodent

brain where appropriate, and to consider these systems within the context of the anatomical pathways in which they participate.

NEUROANATOMY OF THE DOPAMINE SYSTEM

The precursor for dopamine (DA), and all catecholamines, is the amino acid tyrosine. The rate-limiting step in DA synthesis is the conversion of tyrosine to

L-dihydroxyphenylalanine (L-dopa) by the enzyme tyrosine hydroxylase. DA is then formed by decarboxylation of L dopa via the enzyme L-aromatic amino acid

decarboxylase. DA neurotransmission is terminated through the actions of the dopamine transporter (DAT) (Jaber et al. 1997), although in some areas where

the amount of DAT is low, metabolism also plays a role. The DAT accomplishes this task by transporting DA back into the nerve terminal. DA, and all

catecholamines, can also be deactivated by degradation via the enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) (Cooper et al.

1996). MAO metabolizes DA into its aldehyde metabolite, and COMT breaks down DA to 3-methoxytyramine. The role of COMT in regulating DA levels appears

to depend on brain region (see subsection below titled “Projection Sites”) as well as on the presence of two isoforms of the enzyme created by a

valine-for-methionine substitution at codon 108/105 in the COMT gene (Chen et al. 2004).

Antibodies against DA, tyrosine hydroxylase, and DAT have all been used to map the locations of DA cell bodies, dendrites, and axons (Akil and Lewis 1993;

Gaspar et al. 1989; Lewis et al. 1988a, 2001; Williams and Goldman-Rakic 1993). A detailed description of the DA system in the primate brain can be found in

Lewis and Sesack (1997).

Cell Locations

The majority of DA cells, which synthesize approximately three-quarters of all the DA in the brain, are located in the anterior midbrain or mesencephalon

(Figure 4–1). Although the mesencephalic DA neurons of the primate brain have been parcellated into distinct nuclei, most of these cell groups are

interconnected by regions that contain a mixture of cell bodies with different morphological characteristics. These features make it difficult to draw precise

boundaries between nuclei, and most investigators agree that DA neurons form a continuum (Moore and Bloom 1978) that extends caudally from the

mammillary bodies to the pedunculopontine nucleus.

FIGURE 4–1. Projections of dopamine-, norepinephrine-, serotonin-, and acetylcholine-containing neurons in the human brain.Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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SN = substantia nigra; VTA = ventral tegmental area.

Source. Adapted from Heimer 1995.

The substantia nigra contains the majority of DA neurons in the primate brain and is subdivided into two main regions, the substantia nigra pars compacta

and the substantia nigra pars reticulata (Figure 4–2) (Arsenault et al. 1988; Felten and Sladek 1983). The DA neurons in the substantia nigra pars compacta

form a dense zone located in the dorsal region of the substantia nigra. Some DA neurons are located along the dorsal portion of the substantia nigra pars

compacta in an area referred to as the pars dorsalis (Poirier et al. 1983). The neurons of the monkey substantia nigra pars compacta are considered to

correspond to the A9 region in the rodent (Dahlström and Fuxe 1964). The caudal substantia nigra pars compacta has distinct columns of cells that extend

deeply into the ventrally located substantia nigra pars reticulata (Haber and Fudge 1997). Most neurons within the substantia nigra pars reticulata do not

contain DA and use -aminobutyric acid (GABA) as a neurotransmitter (Smith et al. 1987).

FIGURE 4–2. Low-power darkfield photomicrograph of a coronal section through macaque monkey brain processed for dopamine transporter (DAT)

immunoreactivity.Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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Consistent with its localization to dopaminergic structures, intense DAT immunoreactivity (DAT-IR) is evident in the substantia nigra pars compacta (SNc) and pars reticulata

(SNr), as well as in the nigrostriatal projection to the caudate (Cd) and putamen (Pt) nuclei. Also note the marked differences in density of DAT-IR axons across the cortical

regions on this section. DAT-IR axons are also present in areas not traditionally thought to contain DA axons, such as the dentate gyrus (DG) and the thalamus (Th). Scale

bar = 2.0 mm. CgS = cingulate sulcus; CS = central sulcus; DA = dopamine; LS = lateral sulcus; STS = superior temporal sulcus.

Source. Reprinted from Lewis DA, Melchitzky DS, Sesack SR, et al: “Dopamine Transporter Immunoreactivity in Monkey Cerebral Cortex: Regional, Laminar and

The neurons within these subdivisions of the substantia nigra differ in their expression of the messenger RNAs (mRNAs) for both tyrosine hydroxylase and

DAT. For example, the substantia nigra pars compacta neurons have higher levels of both tyrosine hydroxylase and DAT mRNAs than do cells in the substantia

nigra pars dorsalis (Haber et al. 1995). This difference is of interest, given that the neurons in the substantia nigra pars compacta and substantia nigra

dorsalis project to different brain regions (see subsection below titled “Projection Sites”). Interestingly, tyrosine hydroxylase mRNA levels in the substantia

nigra pars dorsalis and ventral cell columns are associated with the COMT genotype. Specifically, individuals with the val/val genotype express higher levels

of tyrosine hydroxylase mRNA than do individuals with the val/met genotype (Akil et al. 2003).

The ventral tegmental area, which is located immediately medial to the substantia nigra, contains DA neurons that are smaller and less densely packed than

those in the substantia nigra pars compacta (Arsenault et al. 1988). This group of neurons corresponds to the A10 group of Dahlström and Fuxe (1964), but

the boundaries of this region are less well developed in primates than in rodents. As in the substantia nigra dorsalis, DA neurons in the ventral tegmental area

contain lower levels of both tyrosine hydroxylase and DAT mRNA than do cells in the substantia nigra pars compacta (Haber et al. 1995).

A third group of DA neurons, the retrorubral area, resides in the caudal midbrain at the level of the medial lemniscus (Arsenault et al. 1988). This group of

neurons corresponds to the A8 group of Dahlström and Fuxe (1964). The DA neurons in the retrorubral area are smaller and more dispersed than those

located in the substantia nigra (Arsenault et al. 1988).

Several hypothalamic nuclei, including the arcuate, periventricular, paraventricular, and supraoptic nuclei, also contain DA neurons (Arsenault et al. 1988).

These DA cell groups correspond to the A11–A15 groups of Dahlström and Fuxe (1964). The DA neurons located within the hypothalamus differ from those

located in the mesencephalon in at least two ways. First, the projections of hypothalamic DA neurons are much shorter, extending only to the intermediate

lobe of the pituitary and the median eminence. Second, unlike the DA neurons in the substantia nigra, ventral tegmental area, and retrorubral area, most of

the DA neurons in the hypothalamus do not express the DAT protein (Ciliax et al. 1995, 1999).

Interestingly, recent studies using large-scale gene expression profiling techniques have revealed differences in gene expression across the various groups of

DA neurons (Greene 2006). For example, genes involved in energy metabolism and mitochondria are more highly expressed in neurons of the substantia

nigra than in neurons of the ventral tegmental area (Chung et al. 2005). This suggests that DA neurons in the substantia nigra may rely more on oxidative

energy metabolism, are under greater metabolic stress, and thus may be more vulnerable to degeneration, such as in Parkinson’s disease (Greene et al.

2005).

Projection Sites

The striatum, including the caudate, putamen, and nucleus accumbens, is a major projection target of the DA neurons in the substantia nigra (see Figure

4–2). Indeed, this nigrostriatal projection is the largest DA system projection in the brain. Specifically, DA neurons in the substantia nigra pars compacta

provide the majority of this projection, with cells in the substantia nigra dorsalis, ventral tegmental area, and retrorubral area furnishing minor projections to

the striatum (Haber and Fudge 1997).

The cerebral cortex is another major projection site of DA neurons, and this projection arises from cells within the substantia nigra dorsalis, ventral tegmental

area, and retrorubral area (Lewis et al. 1988b; Williams and Goldman-Rakic 1998). Although early studies suggested that DA projections to the neocortex in

the primate were restricted to frontal and temporal regions, it has since been demonstrated that essentially all cortical regions in the primate are innervated

by DA axons, although the density of innervation differs substantially across regions (Gaspar et al. 1989; Lewis et al. 1987, 2001; Williams and Goldman-Rakic

1993). In both nonhuman primate and human brains, the motor and premotor cortices, as well as certain areas of the prefrontal (Figure 4–3) and posterior

parietal cortices, contain a high density of DA axons. In these areas, DA axons are present in all cortical layers. In the prefrontal cortex, areas 9 and 24

contain the greatest density of DA axons; areas 11, 12, 13, and 25 have an intermediate density; and areas 10 and 46 have the lowest density of DA axons

(Figure 4–4). The presence of dense DA innervation in some areas of prefrontal cortex and the well-documented deficits in prefrontal cortical activity in

schizophrenia suggest that there may be an abnormality in the DA axons in the prefrontal cortex of patients with schizophrenia. Indeed, postmortem studies

indicate that the total lengths of tyrosine hydroxylase- and DAT-containing axons are significantly reduced in the dorsolateral prefrontal cortex of patients

with schizophrenia (Akil et al. 1999). These findings suggest that the cortical DA signal might be diminished in schizophrenia as a result of reduced content of

tyrosine hydroxylase per axon, reduced density of DA axons, or both. Other cortical regions, such as association areas in the temporal cortex within the

lateral sulcus (see Figure 4–2), contain intermediate levels of DA axons, whereas primary sensory cortices (e.g., visual cortex) generally have low densities of

DA axons (Lewis et al. 1987, 2001). Furthermore, DA axons are present only in layers 1 and 6 in the sparsely innervated sensory regions and in layers 1–3

and 5–6 in the regions that have a moderate density of DA axons.

FIGURE 4–3. Darkfield photomicrographs of (A) tyrosine hydroxylase–, (B) dopamine -hydroxylase–, (C) choline acetyltransferase–, and (D)

serotonin-immunoreactive axons in area 9 of macaque monkey prefrontal cortex.Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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Note the differences in relative density and the distinctive laminar distribution of each afferent system. Scale bar = 200 m. WM = white matter.

Source. Adapted from Lewis et al. 1992.

FIGURE 4–4. Schematic representation of coronal sections from macaque monkey prefrontal cortex illustrating the relative densities of dopamine,

norepinephrine, serotonin, and acetylcholine axons.

Numbers refer to the cortical areas described by Walker (1940). CS = cingulate sulcus; LO = lateral orbital sulcus; MO = medial orbital sulcus; PS = principal sulcus; RS =

rostral sulcus.

Source. Adapted from Lewis 1992.

The regional and laminar distributions of DA axons in the primate cerebral cortex differ from those present in the rodent. For example, DA innervation of the

rodent cortex is principally restricted to the medial prefrontal and anterior cingulate regions (Berger et al. 1991), in contrast to the widespread DA

innervation of the primate cerebral cortex (Lewis et al. 1987, 2001). This expansion of cortical DA innervation in the primate correlates with an increased

number of neurons in the ventral mesencephalon (Bjorklund and Dunnett 2007). At the laminar level, DA axons are denser in layers 1–3 in the primate (see

Figure 4–3), whereas DA axons in the rodent are confined to layers 5–6. The expansion of DA innervation in primates to additional areas, such as sensory and

motor cortices, suggests that DA has additional functions, such as the processing of sensorimotor information, in the human brain, which may be important in

movement disorders like Parkinson’s disease (Berger et al. 1991).

Ultrastructural investigations of DA-containing axon terminals in the primate cortex have revealed that many do not form conventional synaptic

specializations (Beaudet and Descarries 1984; Smiley and Goldman-Rakic 1993). In addition, DA receptors have been identified on spines that are not in

direct contact with DA-containing axon terminals (Smiley et al. 1994), and the DA transporter has been localized at a distance from synaptic sites (Lewis et al.

2001; Sesack et al. 1998). For example, in rodent and primate prefrontal cortex, the DA transporter is localized in preterminal axons as opposed to axon

terminals (where it is heavily localized in the striatum), limiting the ability of the transporter to regulate extracellular DA levels. In association with this

difference, COMT appears to have a more significant role in regulating DA levels in the prefrontal cortex than in subcortical structures (Tunbridge et al. 2004).Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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Polymorphisms in the COMT gene lead to protein products with marked differences in enzymatic activity (Chen et al. 2004). Thus, the COMT genotype

determines DA levels in the prefrontal cortex and may be important in functions in which the level of DA activity at D1 receptors plays a role (e.g., working

memory). Indeed, individuals with the COMT Val allele (high enzyme activity, low DA levels) perform poorly on working memory tasks compared with

individuals with the COMT Met allele (low enzyme activity, high DA levels) (Egan et al. 2001), and it has been suggested that th e COMT genotype is important

in the etiology and pathogenesis of schizophrenia (Lewandowski 2007).

Besides the striatum, other subcortical structures, such as the amygdala and the hippocampus, receive projections from DA neurons. In the amygdala, DA

axons originating from the ventral tegmental area and substantia nigra dorsalis are predominantly found in the central, basal, and lateral nuclei (Ciliax et al.

1999). In rodents, a projection from the ventral tegmental area and substantia nigra pars compacta to the hippocampus has been demonstrated. A similar

projection has not been reported in primates. However, tyrosine hydroxylase- and DAT-immunoreactive axons have been localized only to the dentate gyrus

of the hippocampus in the macaque monkey (Lewis et al. 2001; Samson et al. 1990). DA axons have also been identified in the primate thalamus (Melchitzky

and Lewis 2001; Sanchez-Gonzalez et al. 2005) and cerebellum (Melchitzky and Lewis 2000), two brain regions traditionally thought not to receive DA

innervation (Moore and Bloom 1978; Steriade et al. 1997). In the thalamus, the mediodorsal, midline, lateral posterior, and ventral lateral nuclei contain the

greatest density of DA axons (Melchitzky and Lewis 2001; Sanchez-Gonzalez et al. 2005). Within the mediodorsal nucleus, the ventrolateral portion, which

includes both the densocellular and the parvocellular subdivisions, has the highest density of DAT-immunoreactive axons (Figure 4–5). The DA projections to

the thalamus arise from DA neurons in the substantia nigra pars dorsalis, ventral tegmental area, and retrorubral area (Melchitzky et al. 2006;

Sanchez-Gonzalez et al. 2005) as well as from hypothalamic DA neurons (Sanchez-Gonzalez et al. 2005). The widespread origins of the thalamic DA

projections have led to the proposal of a novel dopaminergic system (Sanchez-Gonzalez et al. 2005); however, other evidence indicates that the thalamic

projections share anatomical features with the mesocortical DA system (Melchitzky et al. 2006). In the cerebellum, DAT-immunoreactive axons have been

localized only to the granule cell layer of the vermis, with lobules VIIIB and IX showing the greatest density of labeled axons (Figure 4–6). Given that both

the mediodorsal nucleus of the thalamus and the posterior vermis of the cerebellum are areas reported to be dysfunctional in schizophrenia (Andreasen et al.

1996; Popken et al. 2000; Tran et al. 1998; Young et al. 2000), the identification of DA axons in these brain regions may be of importance to the

pathophysiology and treatment of this disease.

FIGURE 4–5. Darkfield photomicrographs of adjacent sections through the caudal part of the mediodorsal thalamic nucleus in macaque monkey labeled for

(A) dopamine transporter (DAT), (B) tyrosine hydroxylase (TH), and (C) dopamine -hydroxylase (DBH).

Note that the DAT- and TH-immunoreactive axons are primarily located in the ventral portion of the mediodorsal thalamic nucleus. In contrast, DBH-immunoreactive axons

are present throughout the mediodorsal thalamic nucleus. Scale bar = 700 m. dc = densocellular; pc = parvocellular.

Source. Reprinted from Melchitzky DS, Lewis DA: “Dopamine Transporter–Immunoreactive Axons in the Mediodorsal Thalamic Nucleus of the Macaque Monkey.” Neuroscience

FIGURE 4–6. Darkfield photomicrographs of (A) dopamine transporter (DAT)–, (B) tyrosine hydroxylase (TH)–, and (C) dopamine -hydroxylase

(DBH)–immunoreactive axons in adjacent sections through vermal lobule VIIIB of macaque monkey cerebellum.

Note that both the TH- and DAT-immunoreactive axons are primarily restricted to the granule cell layer (GC), with some clusters of axons extending into the Purkinje cell

layer. TH-immunoreactive axons are also present in the molecular layer (ML), but no DAT-immunoreactive axons are detectable in this layer. In contrast,

DBH-immunoreactive axons are distributed across all layers. In addition, the restricted lobular distribution of DAT-immunoreactive axons is illustrated by the marked paucity

of these axons in the GC (asterisks in B) of the folium across the white matter, whereas the density of DBH-immunoreactive axons does not seem to differ across lobules.

Scale bar = 150 m.

Source. Reprinted from Melchitzky DS, Lewis DA: “Tyrosine Hydroxylase- and Dopamine Transporter–Immunoreactive Axons in the Primate Cerebellum: Evidence for a

Receptors

Five genes encoding five unique DA receptors have been identified. All of these receptors belong to the superfamily of seven-transmembrane-domain GPrint: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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protein–coupled receptors. As implied by the name, the receptor protein spans the plasma membrane seven times, and these receptors are linked to specific

G proteins, through which activation of these receptors affects intracellular mechanisms in the postsynaptic cell. Pharmacologically, these receptors can be

grouped into two general classes, the D1 and D2 subtypes. The D1 receptor subtype includes the D1 and D5 receptors, and the D2 receptor subtype consists of

the D2, D3, and D4 receptors. Interestingly, the D5 receptor has a 10-fold higher affinity for DA than the D1 receptor, although the D1 receptor is more

prevalent (described in detail later in this section) (Meador-Woodruff 1994). The D2 subtype receptors are targeted by many antipsychotic medications.

The mRNAs encoding the different DA receptors have distinct anatomical distributions. The following description of the localization of DA receptor mRNA is

based mostly on data from rodents, but data from studies in primates are included when available. In addition, data from autoradiographic and/or

immunocytochemical investigations of receptor and protein localization, respectively, are discussed where appropriate. D1 receptor mRNA is present at high

levels in the caudate, putamen, nucleus accumbens, and amygdala and at lower levels in the septal region, hippocampus, thalamus, cerebellum, and cerebral

cortex (Hurd et al. 2001; Jaber et al. 1996; Meador-Woodruff et al. 1996). In the cerebellum, D1 receptor mRNA is expressed in the anterior lobules within the

granular cell layer (Mengod et al. 1991). D1 receptor mRNA is found in all layers of the cerebral cortex, but cortical regions exhibit different laminar patterns

(Meador-Woodruff et al. 1991). Brain regions that do not contain D1 receptor mRNA include the substantia nigra pars compacta and the ventral tegmental

area (Meador-Woodruff 1994). In addition, the D1 receptor has been localized, using a type-specific antibody and immunocytochemistry, in the primate

prefrontal and premotor cortices and in the hippocampus (Bergson et al. 1995). In these regions, the D1 receptor is predominantly located postsynaptically in

dendritic spines. The D1 receptor protein has also been localized to the medium-sized GABA neurons in the caudate nucleus (Bergson et al. 1995). A positron

emission tomography study revealed an increase in the binding of NNC112, a D1 receptor ligand, in drug-free and drug-naive schizophrenia patients,

consistent with a compensatory D1 receptor upregulation in response to reduced DA levels (Abi-Dargham et al. 2002). Thus, both postmortem anatomical and

neuroimaging studies indicate decreased DA in the prefrontal cortex of subjects with schizophrenia. Brain regions that do not contain D1 receptor mRNA

include the substantia nigra pars compacta and the ventral tegmental area (Hurd et al. 2001; Meador-Woodruff 1994).

Regions of the brain that contain high levels of D2 receptor mRNA include the caudate, putamen, nucleus accumbens, ventral tegmental area, and substantia

nigra (Hurd et al. 2001; Jaber et al. 1996; Meador-Woodruff et al. 1996). Within the latter two areas, D2 receptors are predominantly located presynaptically

and where they regulate dopamine synthesis and release. The D2 receptor mRNA is present at lower levels in the septal region, amygdala, hippocampus,

thalamus, cerebellum, and cerebral cortex (Jaber et al. 1996; Meador-Woodruff 1994). In the cerebellum, lobules IX and X, which contain DA axons

(Melchitzky and Lewis 2000), have the greatest concentrations of D2 receptor mRNA (Mengod et al. 1992) and also express the D2 receptor protein (Khan et

1998). Limbic regions of the brain, such as the nucleus accumbens, have the highest density of D3 receptor mRNA in the brain (Jaber et al. 1996;

Meador-Woodruff 1994). The substantia nigra, ventral tegmental area, septal region, thalamus, cerebellum, and cerebral cortex contain moderate to low

levels of the mRNA for this receptor. In addition, lobules 9 and 10 of the cerebellar vermis express the D3, as well as the D2, receptor mRNA (Diaz et al. 1995;

Mengod et al. 1992).

The D4 and D5 receptor mRNAs are not as highly expressed in the brain as are the mRNAs for the D1–D3 receptors (Jaber et al. 1996; Meador-Woodruff 1994).

Low levels of D4 receptor mRNA have been localized to the substantia nigra, nucleus accumbens, ventral tegmental area, hippocampus, amygdala, and

cerebral cortex. In addition, the D4 receptor protein is found in the cerebral cortex and hippocampus, where it is localized to both pyramidal and

GABA-containing cells (Mrzljak et al. 1996). The D5 receptor is the least widely distributed DA receptor, with low levels of mRNA present in the hippocampus,

cerebellum, and thalamus (Jaber et al. 1996; Meador-Woodruff 1994). However, visualization of D5 receptors with a type-specific antibody and

immunocytochemistry has revealed that in the primate brain, the D5 receptor is located in prefrontal, premotor, and mesolimbic cortices, as well as in the

hippocampus (Bergson et al. 1995).

NEUROANATOMY OF THE NOREPINEPHRINE SYSTEM

The initial steps in the biosynthesis of norepinephrine (NE) are identical to those for DA. The rate-limiting step is the conversion of the amino acid tyrosine

into L-dihydroxyphenylalanine, or L-dopa, via the enzyme tyrosine hydroxylase. NE is then formed from dopamine by the enzyme dopamine- -hydroxylase. As

for the other monoamines, NE neurotransmission is terminated through the actions of the NE transporter protein. A detailed description of the primate NE

system can be found in Foote (1997).

Cell Locations

NE-containing neurons in the central nervous system are located predominantly in the medulla and pons (see Figure 4–1). The principal noradrenergic cell

group is the locus coeruleus, the largest group of NE-containing neurons in the mammalian brain. In addition, it is the source of most of the ascending

noradrenergic projections. The locus coeruleus is composed of a compact collection of neurons located in the dorsal pons, medial to the mesencephalic tract

of the trigeminal nerve. In primate species, NE-containing neurons of the locus coeruleus, like the DA neurons of the substantia nigra, are heavily pigmented

with neuromelanin, particularly in mature individuals (Manaye et al. 1995). Consistent with the role of NE in mood disorders, decreases in the neuronal

density of locus coeruleus neurons have been reported in postmortem studies of patients with depression (Ressler and Nemeroff 2000).

NE-containing cells are also present in the caudal medulla, including the intermediate reticular zone and the lateral paragigantocellularis nucleus, as well as in

the nucleus ambiguus. Collectively, these groups are known as the lateral ventral tegmental fields (Cooper et al. 1996).

Projection Sites

The cerebral cortex is a major recipient of noradrenergic projections, specifically those coming from the locus coeruleus (Gatter and Powell 1977; Porrino and

Goldman-Rakic 1982). All areas of the cerebral cortex receive these projections; however, certain areas have higher densities of NE axons than other areas.

For example, primary somatosensory and visual cortices have a very high density of NE axons, whereas prefrontal cortical areas (see Figure 4–3) are less

densely innervated (Lewis and Morrison 1989; Morrison et al. 1982). Within the prefrontal cortex, the distribution of NE axons is similar to that of DA axons,

with areas 9 and 24 having the highest density of NE axons; areas 11, 12, 13, and 25 having an intermediate density of NE axons; and areas 10 and 46 having

the lowest density of NE axons (see Figure 4–4). These innervation patterns exhibit interesting comparisons and contrasts with those of DA axons. For

example, the primary motor cortex contains high densities of both DA and NE axons, whereas the adjacent primary somatosensory cortex contains a very high

density of NE axons but a low density of DA axons (Lewis and Morrison 1989; Morrison et al. 1982).

Other brain regions innervated by the locus coeruleus include the thalamus, cerebellar cortex, hypothalamus, and amygdala. Within the thalamus, the

different nuclei display varied densities of NE axons. For example, in the primate, the mediodorsal thalamic nucleus contains a high density of NE axons (see

Figure 4–5) (Melchitzky and Lewis 2001), whereas the lateral geniculate nucleus is sparsely innervated (Morrison and Foote 1986). By contrast, the different

regions of the cerebellar cortex (i.e., the vermis, intermediate zones, and hemispheres) are all moderately innervated by noradrenergic axons (see Figure

4–6) (Melchitzky and Lewis 2000). In addition, unlike the distribution of DA axons, NE axons are found in both the granule cell and molecular layers. Within

the hypothalamus and amygdala, the paraventricular and basolateral nuclei, respectively, contain the highest density of NE axons in these structures

(Ginsberg et al. 1993; Li et al. 2001).

The noradrenergic nuclei in lateral tegmental fields appear to project exclusively to the brain stem and spinal cord in primates. By contrast, in rodents, these

nuclei have been shown to also project to subcortical structures, such as the amygdala and septum (Delfs et al. 2000; Zardetto-Smith and Gray 1995).

Receptors

The receptors that recognize NE, the and adrenoreceptors, belong to the G protein superfamily of receptors. Thus, similar to DA, NE elicits responses in the

postsynaptic cell via G protein–mediated second-messenger systems. Both and adrenoreceptors have two subtypes, namely the 1 and 2 adrenoreceptors

and the 1 and 2 adrenoreceptors (Cooper et al. 1996). All of these receptors are widely distributed across the cerebral cortex, although their regional and

laminar patterns differ. For example, in primate prefrontal cortex, autoradiography using appropriate ligands demonstrated that the 1 and 2

adrenoreceptors are prominent in layers 1–superficial 3, whereas the highest density of 1 and 2 adrenoreceptors is in layers deep 3–4 (Goldman-Rakic et al.

1990). Furthermore, in the human brain, 1 adrenoreceptors are also present in high density in the cortex, as well as in regions of the thalamus,

hypothalamus, and hippocampus (Palacios et al. 1987). Stimulation of 2 adrenoreceptors in the frontal cortex appears to improve attention, raising the

possibility of adrenergic system–targeted therapies for attention-deficit disorders and disorders associated with cognitive deficits, such as Alzheimer’s

disease and schizophrenia (Stahl 1998).Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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In the rodent, the mRNA for the 1 adrenoreceptor is localized to many areas, including cerebral cortex, reticular nucleus of the thalamus, deep cerebellar

nuclei, brain stem nuclei, and spinal cord, while the mRNA for the 2 adrenoreceptor has a more restricted distribution to the olfactory bulb, hippocampus,

cerebellar cortex, and intralaminar thalamic nuclei (Nicholas et al. 1993). Autoradiographic studies have also revealed high densities of the adrenoreceptors

in the striatum, the hippocampus and the cerebral cortex in human brain (Pazos et al. 1985). Lower densities of adrenoreceptors have been found in the

thalamus, hypothalamus, and amygdala and the molecular and granule cell layers of the cerebellar cortex (Pazos et al. 1985). Dysregulation of noradrenergic

transmission via adrenoreceptors has been implicated in the pathophysiology of depression. For example, postmortem studies have revealed increased

binding of adrenoreceptors in the frontal cortex of suicide victims (Mann et al. 1986).

NEUROANATOMY OF THE SEROTONIN SYSTEM

Only 2% of the serotonin (5-hydroxytryptamine [5-HT]) in the body is found in the brain. The neurons within the brain synthesize 5-HT, starting with the

amino acid tryptophan, which is then hydroxylated via the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan. 5-HT is then formed by

decarboxylation of 5-hydroxytryptophan. Similar to DA, reuptake via the serotonin transporter (SERT) is the principal mechanism for terminating

serotonergic neurotransmission. SERT also regulates the availability—and hence the signaling potential—of released 5-HT. Consequently, the strength of 5-HT

activity at 5-HT receptors is inversely proportional to the number of functional SERT molecules present at the presynaptic membrane. Selective serotonin

reuptake inhibitors (SSRIs) and related antidepressant drugs exploit this relationship by blocking the reuptake of 5-HT by SERT, thus increasing the levels of

5-HT in the synaptic cleft. In humans, the gene encoding for SERT exists in both long and short forms, with the short form resulting in lower levels of SERT

expression. Azmitia and Gannon (1986) have provided a detailed description of the primate 5-HT system.

Cell Locations

The highest concentration of 5-HT-containing neurons in the mammalian brain is found in the raphe nuclei of the brain stem (see Figure 4–1). The cellular

morphology and anatomical distribution of 5-HT neurons indicate that the raphe nuclei can be divided into rostral and caudal brain stem groups in the monkey

and human brain stem (Hornung 2003). The principal subdivisions of the rostral raphe nuclei consist of the median raphe, dorsal raphe, and caudal linear

nuclei located in the pons and midbrain. The caudal raphe nuclei consist of the raphe pallidus, raphe obscurus, and raphe magnus located in the caudal pons

and medulla. The rostral raphe nuclei provide the bulk of the ascending axonal projections to the cerebral cortex and other subcortical structures, whereas

the caudal raphe nuclei give rise to descending projections to the lower brain stem and spinal cord (Hornung 2003). Because of the functional and clinical

importance of the 5-HT input to the cerebral cortex and limbic forebrain provided by the rostral nuclei, the following anatomical description of the 5-HT

system will focus on the rostral raphe nuclei and their axonal projections.

The most rostral 5-HT neurons are located in the interpeduncular nucleus of the ventral mesencephalon (Hornung 2003). The caudal linear nucleus, located

dorsal and caudal to the interpeduncular nucleus, lies between the red nuclei and contains both 5-HT and DA neurons. The most diverse of the raphe nuclei is

the dorsal raphe nucleus (Baker et al. 1990). It is located in the central gray matter ventral to the cerebral aqueduct and fourth ventricle. On the basis of the

topography and density of neurons in the primate, the dorsal raphe can be subdivided into five distinct subnuclei. Of these subnuclei, the ventrolateral

subnucleus exhibits the highest density of 5-HT neurons in the entire brain stem (Baker et al. 1990). Postmortem studies have revealed abnormalities such as

increased mRNA and protein levels of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of 5-HT, in the dorsal raphe nucleus of suicide victims

(Bach-Mizrachi et al. 2006). The median raphe extends from the caudal midbrain into the rostral pons (Tork and Hornung 1990). Serotonin neurons in the

rostral level of the median raphe are densely packed along the midline, whereas at caudal levels, the nucleus expands laterally to form its characteristic

barrel-shaped appearance. The barrel-like appearance is formed by the development of the paramedian raphe nuclei, which straddle the midline and contain

both 5-HT neurons and 5-HT axons that arise from more caudal levels.

Projection Sites

The cerebral cortex is a major recipient of 5-HT axons arising from the mesencephalon. The heaviest projections to the frontal cortex, including prefrontal

(see Figure 4–3) and motor cortices, arise from the dorsal raphe (M. A. Wilson and Molliver 1991). The median raphe and supralemniscal group project

equally to the parietal, occipital, and frontal cortices. Unlike DA axons in the DA system, 5-HT axons are homogeneously distributed across different cortical

areas, with the greatest density of axons usually present in the middle cortical layers (Morrison and Foote 1986). Furthermore, within cortical areas such as

the prefrontal cortex, the density of 5-HT axons across regions is homogeneous (see Figure 4–4).

Although this area has been less well studied in primates, investigations in rodents suggest that the median raphe and dorsal raphe projections to the

cerebral cortex are distinct in a number of respects (Mamounas and Molliver 1991). The cortical 5-HT axons originating from the median raphe are

characterized by the presence of large spherical varicosities with thin intervaricose segments that give these axons a beaded appearance. In contrast, cortical

axons originating from the dorsal raphe are fine and tortuous, with irregularly spaced small varicosities. Most cortical regions contain both types of 5-HT

axons; however, the intracortical distribution of 5-HT axons is not uniform. For example, in the primate prefrontal cortex, the fine axons are present in all

layers but are more abundant in layers 3–6, whereas the beaded axons predominate in layers 1–2 (Smiley and Goldman-Rakic 1996). These distinct

morphological features of 5-HT axons, together with the unique topographical distributions, suggest that different functional roles for the two 5-HT fiber

systems may exist. For example, in both rodents and primates, administration of amphetamine derivatives, such as methylenedioxyamphetamine and

p-chloroamphetamine, causes selective degeneration of fine 5-HT-containing axons, whereas the beaded axons are spared (Mamounas and Molliver 1991;

Molliver et al. 1990).

Interestingly, the effects of SSRIs differ based on the brain region and cellular localization of SERT. For example, blocking SERT in 5-HT projection fields (e.g.,

in the cerebral cortex) increases 5-HT levels and signaling at all available 5-HT receptors. By contrast, blocking SERT at the 5-HT cell body level (e.g., in the

raphe nuclei) leads to increased activation of 5-HT1 autoreceptors (see subsection below titled “Receptors”), ultimately resulting in reduction of overall 5-HT

function. Eventually, 5-HT output is increased through desensitization of 5-HT1 autoreceptors by SSRIs.

With regard to 5-HT synapses in primate cortex, the presence of 5-HT-labeled varicosities does not necessarily correspond to 5-HT synaptic specializations. In

fact, it has been reported that more than three-quarters of 5-HT varicosities in the primate cortex do not form identifiable synaptic specializations, even

though many had synaptic vesicles and accumulated 5-HT immunoreactivity (Smiley and Goldman-Rakic 1996). These observations suggest that 5-HT release,

like that of DA, may occur at sites other than identified synapses and support the concept that nonsynaptic mechanisms of 5-HT neurotransmission are

present in the primate cortex.

The raphe nuclei also project to a number of subcortical structures. The rostral group, including the caudal linear and dorsal raphe nuclei, project to the

caudate, putamen, substantia nigra, and thalamus. In the primate, the 5-HT innervation of the thalamus is heterogeneous and widespread. The midline,

rostral intralaminar, and reticular nuclei are the most densely innervated, whereas the ventral anterior and habenula are sparsely innervated (Lavoie and

Parent 1991). The median raphe and the interfascicular subnucleus of the dorsal raphe project to limbic structures such as the hippocampus, amygdala, and

septum. Serotonin neurons in both the median raphe and dorsal raphe contain highly collocated axons that innervate multiple terminal fields. This axonal

organization pattern suggests that functionally related nuclei can be innervated by the same group of 5-HT neurons or even the same individual neuron.

Receptors

Physiological and biochemical studies have revealed that multiple receptors exist for 5-HT and that many of these receptors have subtypes. To date, 14 5-HT

receptors have been identified. The current classification of 5-HT receptors is based on structural characteristics and the second-messenger systems that are

utilized. All but one of the 5-HT receptors belong to the G protein receptor superfamily. The exception is the 5-HT3 receptor, which belongs to the

ligand-gated ion channel family (Peroutka 1997).

As with the other monoamine systems, the distribution of 5-HT receptors has been studied mostly in rodents by localization of receptor mRNAs. However,

studies conducted in human subjects reveal receptor mRNA distributions similar to those in rodents. The 5-HT1 receptor has six subtypes, 5-HT1A–F (Peroutka

1997). Several of the 5-HT1 subtypes—5-HT1A, 5-HT1B, and 5-HT1D—appear to also function presynaptically, because the mRNA for these subtypes has been

localized to 5-HT-containing neurons in both the dorsal and median raphe. Thus, these receptors also function as autoreceptors, regulating the firing of raphe

neurons. In addition, 5-HT1A and 5-HT1B receptors, as revealed by immunocytochemistry and autoradiography, are present in the cerebral cortex as well as

other projection sites of the dorsal raphe and median raphe (DeFelipe et al. 2001; Goldman-Rakic et al. 1990; Jakab and Goldman-Rakic 2000; Mengod et al.

1996).Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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The 5-HT2 receptor has three subtypes, 5-HT2A–C (Peroutka 1997). The most widely studied of these is the 5-HT2A subtype, the mRNA of which is most

abundant in the cerebral cortex. In most cortical areas, layers 1 and 3–4 have a higher density of 5-HT2A mRNA levels than layers 2 and 5–6 (Lopez-Gimenez

et al. 2001b). In monkey prefrontal cortex, the 5-HT2A receptor appears to be expressed by pyramidal cells as well as in the parvalbumin-containing subclass

of nonpyramidal neurons (Jakab and Goldman-Rakic 2000), which provide potent inhibitory input to pyramidal cells. Subcortical structures, including the

caudate, putamen, substantia nigra, and inferior olive, also express 5-HT2A mRNA (Lopez-Gimenez et al. 2001b). The anatomical localization of the 5-HT2B

receptor has not been extensively studied, but the cerebral cortex has been shown to contain the mRNA for this receptor (Mengod et al. 1996). The 5-HT2B

receptor mRNA is also localized to the cerebral cortex, whereas the 5-HT2C receptor mRNA has been identified in the hypothalamus and medulla (Mengod et

1996). The mRNA for the 5-HT2C receptor has been localized to layer 5 of cerebral cortex, nucleus accumbens, caudate, putamen, septal nuclei, diagonal

band, ventral striatum, and extended amygdala (Lopez-Gimenez et al. 2001a). Increased binding of both 5-HT1A and 5-HT2A receptors has been found in the

prefrontal cortex of suicide victims (Mann et al. 1986), possibly representing an upregulation of receptors due to decreased serotonergic transmission.

The 5-HT3 receptor mRNA has been identified in rodent cerebral cortex, where it was found to be collocated with GABA-containing neurons (Tecott et al.

1993). In addition, in monkey prefrontal cortex, the 5-HT3 receptor has been localized to small GABA-containing neurons that also express substance P and

the calcium-binding protein calbindin (Jakab and Goldman-Rakic 2000).

The anatomical distribution of the 5-HT4 receptor has been examined by autoradiography in human brain, and areas with the highest levels of receptors are in

the basal ganglia nuclei (caudate, putamen, nucleus accumbens, globus pallidus, and substantia nigra) and the hippocampus, specifically area CA1 and

subiculum (Varnas et al. 2003). In neocortex, the superficial layers have higher levels of 5-HT4 receptor than the deeper cortical layers.

In rodent brain, the 5-HT7 receptor protein is found in the cerebral cortex, hippocampus, thalamus, and hypothalamus, with a somatodendritic localization in

these areas (Neumaier et al. 2001). In human brain, 5-HT7 receptors, visualized via autoradiography, are also found in the cerebral cortex, hippocampus, and

thalamus, as well as in the caudate and putamen (Martin-Cora and Pazos 2004).

The anatomical localization of the remaining 5-HT receptors (i.e., 5-HT5A–B, 5-HT6) has not been as well studied. However, mRNA for these receptor subtypes

appears to be predominantly localized to subcortical structures, such as the caudate, nucleus accumbens, hippocampus, thalamus, and amygdala.

NEUROANATOMY OF THE ACETYLCHOLINE SYSTEM

Acetylcholine (ACh) is phylogenetically a very old molecule that is widely distributed in eukaryotic as well as prokaryotic cells. Furthermore, ACh is found in

many non-neuronal tissues, in which it appears to modulate basic cellular actions. ACh is formed by the synthesis of acetyl coenzyme A and choline via the

enzyme choline acetyltransferase. Acetyl coenzyme A is available from mitochondria, and choline is obtained through the diet. ACh is rapidly inactivated in the

synaptic cleft by the enzyme acetylcholinesterase. The activity of both choline acetyltransferase and acetylcholinesterase is reduced in the frontal and

temporal cortices of patients with Alzheimer’s disease, and the decrease in choline acetyltransferase activity is associated with the presence of the

apolipoprotein epsilon 4 (ApoE- 4) allele (Lai et al. 2006).

The presence of ACh-containing cell bodies and axons has been demonstrated by the use of histochemical procedures to visualize the acetylcholinesterase

molecule, as well as by the use of specific antibodies directed against choline acetyltransferase. Immunocytochemical identification of ACh-containing axons

using choline acetyltransferase antibodies is the preferred method, because acetylcholinesterase may not be a specific marker of cholinergic structures. A

detailed review of the primate cholinergic system can be found in De Lacalle and Saper (1997).

Cell Locations

ACh-containing neurons are located in two main groups in the brain (see Figure 4–1). The basal forebrain cholinergic complex is located near the inferior

surface of the telencephalon, between the hypothalamus and orbital cortex. This complex includes the medial septal nucleus, the diagonal band of Broca, the

nucleus basalis (also known as the basal nucleus of Meynert), the magnocellular preoptic area, and the substantia innominata. All of these regions are

characterized by the presence of large ACh-containing multipolar neurons (Semba and Fibiger 1989).

The pontomesencephalotegmental cholinergic complex consists of the pedunculopontine nucleus, which is located along the dorsolateral aspect of the

superior cerebellar peduncle, and the laterodorsal tegmental nucleus in the ventral part of the periaqueductal gray. Similar to the cells in the basal forebrain

complex, the pontomesencephalotegmental complex is also characterized by the presence of large ACh-containing cells (Semba and Fibiger 1989).

In addition to these cell groups, ACh-containing neurons are also present in all nuclei of the striatum (i.e., the caudate, putamen, and nucleus accumbens).

However, these cholinergic cells are interneurons and thus do not project out of the striatum (Cooper et al. 1996).

Projection Sites

The cerebral cortex is a major recipient of cholinergic projections, which originate predominantly from the basal forebrain complex. The organization of these

projections in the primate is similar to that in the rodent. In general, these projections are topographically organized, with a distinct population of neurons

projecting to a particular location in the cortex.

The distribution of ACh-containing axons in the cerebral cortex is heterogeneous, with paralimbic areas having the greatest density of ACh-containing axons.

The sensory and association regions of neocortex are less densely innervated by cholinergic axons than are the paralimbic areas. For example, in human

brain, the density of cholinergic axons is lowest in the primary visual cortex; moderate in association areas, including parts of the prefrontal (see Figure 4–3)

and parietal cortices; and highest in the paralimbic entorhinal and cingulate cortices (Mesulam et al. 1992). The density of cholinergic axons also differs

within a cortical region. In monkey prefrontal cortex, there is a rostral to caudal increase in the density of ACh-containing axons, so that area 10 at the frontal

pole has a lower density of cholinergic axons than does area 9, which is less densely innervated than the more caudal area 8B. Furthermore, the more caudal

premotor (area 6) and motor (area 4) cortices have the highest density of ACh-containing axons in the frontal lobe (Lewis 1991). However, cholinergic axons

are distributed homogeneously across prefrontal areas at the same rostrocaudal level (see Figure 4–4).

The distribution of ACh-containing axons across the cortical layers is also heterogeneous. In general, layers 1–2 and 5 have the highest density of cholinergic

axons, whereas layer 4 has the lowest density of ACh-containing axons (Lewis 1991; Mesulam et al. 1992).

The hippocampus is also densely innervated by cholinergic axons. These projections arise from the medial septal and diagonal band of Broca nuclei of the

basal forebrain complex (Kitt et al. 1987). The molecular layer of the dentate gyrus and the CA2, CA3, and CA4 subsectors of the hippocampus contain the

highest densities of ACh-containing axons (Mesulam et al. 1992). Although the densities of ACh-containing fibers in the CA1 subsector and subiculum are

lower than those in the other portions of the hippocampus, they are still more densely innervated than most cortical areas (Mesulam et al. 1992).

The amygdala also receives projections from the basal forebrain cholinergic complex. Within the amygdala, all nuclei are densely innervated by

ACh-containing axons, with the basolateral nucleus having the highest density (Mesulam et al. 1992). Retrograde tracing has demonstrated that this

projection principally arises from the nucleus basalis (Kitt et al. 1987).

In the rodent, the reticular nucleus of the thalamus and the interpeduncular nucleus are densely innervated by cholinergic axons originating from the nucleus

of the diagonal band of Broca and the nucleus basalis, respectively. These projections have not been investigated in the primate (Semba and Fibiger 1989).

The thalamus is densely innervated by cholinergic axons, which originate from the pedunculopontine and laterodorsal tegmental nuclei (Semba and Fibiger

1989). In addition, acetylcholinesterase activity and immunoreactivity for choline acetyltransferase have revealed a heterogeneous distribution of cholinergic

axons within the thalamus. For example, in the primate, the midline, intralaminar, anterodorsal, lateral mediodorsal, and medial pulvinar nuclei contain very

high levels of cholinergic axons (Barbas et al. 1991; Cavada et al. 1995). A similar pattern of cholinergic axons is found in the rodent (Levey et al. 1987).

The pedunculopontine and laterodorsal tegmental nuclei project to other subcortical structures, including the lateral hypothalamus, the superior colliculus,

and the lateral preoptic area. However, these projections have only been investigated in rodents (Semba and Fibiger 1989).

Receptors

ACh receptors have been divided into two main classes, the muscarinic and nicotinic receptors. There are five (M1–M5) subtypes of the muscarinic receptor,

all of which are coupled to G proteins and linked to a variety of second-messenger systems. Neuronal nicotinic receptors are formed from fivePrint: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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membrane-spanning subunits situated around a central pore. The neuronal nicotinic receptor has two subunits, and ; the subunit has seven different

forms, and the subunits that form

combinations include 2– 6 and 2– 4 (Dani and Bertrand 2007). Homomeric and heteromeric nicotinic receptors can be

formed from the 7– 10 subunits. The nicotinic receptors are ionotropic, acting directly on sodium channels.

Most of the studies investigating the localization of ACh receptors in the brain have employed autoradiography, utilizing tritiated nicotine or receptor

subtype-specific ligands. For example, the M1 and M2 receptor subtypes have been shown to be present in many regions of the cerebral cortex, including the

frontal, parietal, and occipital cortices (Flynn and Mash 1993). Specifically, the overall densities of the M1 and M2 receptor subtypes are similar, but the

laminar distributions vary across the cortex (Lidow et al. 1989). In parietal, occipital, and motor cortices, both receptor subtypes are concentrated in the

superficial layers. In contrast, the M1 and M2 subtypes are evenly distributed across the cortical layers in the prefrontal cortex. Subcortical structures show a

varied distribution of muscarinic receptors. The striatum has a high density of M1, M2, and M3 receptors, with M3 receptors localized to the anterior and dorsal

caudate nucleus and M1 receptors more prevalent in the ventromedial caudate and medial globus pallidus (Flynn and Mash 1993). Low levels of M1 and M3

receptors are found in the thalamus, hypothalamus, and brain stem. In Alzheimer’s disease, M1 and M2 receptors, as measured by autoradiography, are

reduced in the frontal cortex and hippocampus, respectively, whereas M3 and M4 receptors appear to be unaffected (Rodriguez-Puertas et al. 1997).

The distribution of tritiated nicotine binding sites is similar in both rat and monkey brains. For example, in both species, dense labeling occurs in sensory- and

motor-related thalamic nuclei, the dentate gyrus of the hippocampus, and layer 3 of the cerebral cortex (Clarke 1989). Furthermore, the anatomical

distributions of mRNA for the nicotinic ACh receptor subunits have been investigated in the monkey brain. The 4 and 2 receptor subunits are the most

widely distributed, with highest densities in the dorsal thalamus and the DA-containing nuclei of the mesencephalon (Han et al. 2000). Consistent with the

well-known involvement of the cholinergic system in Alzheimer’s disease, the densities of 4 and 2 nicotinic receptors are reduced in the temporal and

frontal cortices of patients with this disease (Lai et al. 2006).

Several lines of evidence support a role for the 7 receptor subunit in the pathophysiology of sensory gating deficits in schizophrenia. For example, a

postmortem study has shown that binding of -bungarotoxin, which most likely corresponds to nicotinic receptors containing the 7 subunit (Leonard et al.

2000), is reduced in the hippocampus of patients with schizophrenia (Freedman et al. 1995). In addition, sensory gating deficits are improved by nicotine in

subjects with schizophrenia as well as in their unaffected family members (Adler et al. 1998). Interestingly, unlike control subjects, who show an

upregulation of nicotinic receptors in association with smoking, individuals with schizophrenia exhibit lower binding of nicotinic receptors at every level of

smoking history (Breese et al. 2000).

ENDOCANNABINOID SYSTEM

The endocannabinoid system is an endogenous signaling system composed of endocannabinoids, their receptors, and the proteins involved in their synthesis

and degradation (Pazos et al. 2005). Anandamide and 2-arachidonoylglycerol, the two principal endocannabinoids in the brain, bind to and activate the G

protein–coupled cannabinoid receptors, CB1 and CB2. The CB1 receptor, the predominant endocannabinoid receptor in the brain, mediates most of the

behavioral effects of endogenous and exogenous cannabinoids (Zimmer et al. 1999). The CB2 receptor is principally expressed in non-neural tissues, such as

immune system organs (e.g., spleen). CB1 receptors are located primarily on presynaptic axon terminals and mediate the retrograde signaling of

endocannabinoids in synaptic plasticity processes, such as depolarization-induced suppression of inhibition (Alger 2002).

Distribution of the CB1 receptor is widespread, with many areas of the brain expressing high levels (Figure 4–7). Specifically, the neocortex, hippocampus,

amygdala, globus pallidus, and cerebellum all exhibit high densities of the CB1 receptor (Biegon and Kerman 2001; Eggan and Lewis 2007; Herkenham et al.

1991). Within the primate cerebral cortex, association regions, such as the prefrontal cortex, contain the highest levels of CB1-immunoreactive axons,

whereas primary sensory regions, particularly primary visual cortex, have the lowest densities (Eggan and Lewis 2007). Within the prefrontal cortex,

dorsolateral area 46 contains the highest densities of CB1-immunoreactive axons. The density of CB1-labeled axons in the hippocampus is similar to that in

the prefrontal cortex. Interestingly, within the amygdala, the cortical-like basolateral complex has a higher density of CB1 axons than does the striatal-like

central and medial nuclei (Figure 4–7). Of the basal ganglia nuclei, the globus pallidus has the highest and the striatum the lowest levels of CB1

immunoreactivity. As is evident in Figure 4–7, the thalamus is completely devoid of CB1 axons.

FIGURE 4–7. Brightfield photomicrograph of a coronal section through macaque monkey brain illustrating the distribution of cannabinoid CB1

receptor–immunoreactive axons.Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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Association areas such as the cingulate cortex (area 32), insula (Ig, Idg), auditory association cortex (RP), and entorhinal cortex (EI) have an overall higher density of

CB1-immunoreactive axons than do primary somatosensory areas (areas 3, 1, 2) and primary motor cortex (area 4). Note the distinct differences in laminar distribution of

labeled processes at the boundaries of some cytoarchitectonic regions (arrows). In subcortical structures, the intensity of CB1 immunoreactivity is high in the claustrum (Cl),

the basal and lateral nuclei of the amygdala, and both segments of the globus pallidus (GP); intermediate to low in the caudate (Cd) and putamen (Pu) and the central and

medial nuclei of the amygdala; and not detectable in the thalamus (Th). Scale bar = 2 mm. ABmc = accessory basal nucleus, magnocellular division; ABpc = accessory basal

nucleus, parvicellular division; Bi = basal nucleus, intermediate division; Bmc = basal nucleus, magnocellular division; Bpc = basal nucleus, parvicellular division; CC = corpus

callosum; Cd = caudate; Ce = central amygdaloid nucleus; Cgs = cingulate sulcus; Cl = claustrum; COp = posterior cortical nucleus; cs = central sulcus; EI = entorhinal

cortex, intermediate field; GPe = globus pallidus, external; GPi = globus pallidus, internal; Idg = insula, dysgranular; Ig = insula, granular; ips = intraparietal sulcus; Ldi =

lateral nucleus, dorsal intermediate division; lf = lateral fissure; Lv = lateral nucleus, ventral division; Lvi = lateral nucleus, ventral intermediate division; Me = medial

amygdaloid nucleus; PN = paralaminar nucleus; Pu = putamen; R = rostral auditory area (core primary auditory); rf = rhinal fissure; RM = rostromedial auditory belt; RP =

rostral auditory parabelt; SII = second somatosensory cortex; sts = superior temporal sulcus; TE = inferotemporal cortex; Th = thalamus; TPO = temporal parieto-occipital

associated area in sts.

Source. Reprinted from Eggan SM, Lewis DA: “Immunocytochemical Distribution of the Cannabinoid CB1 Receptor in the Primate Neocortex: A Regional and Laminar

In the neocortex, the CB1 receptor is highly expressed in the subpopulation of GABA-containing inhibitory interneurons (Marsicano and Lutz 1999) that also

synthesize the neuropeptide cholecystokinin (Bodor et al. 2005). In addition, in rodent hippocampus (Katona et al. 1999) and monkey prefrontal cortex

(Melchitzky et al. 2007), CB1-immunoreactive axons have been shown to be collocated with cholecystokinin. This association of CB1 with GABA neurons in the

prefrontal cortex suggests that the endocannabinoid system may be involved in cognitive processing as well as in disorders characterized by impaired

cognition, such as schizophrenia. Indeed, cannabis use impairs cognitive processes such as working memory (D’Souza et al. 2004) and has been associated

with an increased risk for schizophrenia (Smit et al. 2004). In addition, a reduction in CB1 mRNA levels in the prefrontal cortex of subjects with schizophrenia

(Eggan et al. 2008) provides further evidence for a role of the endocannabinoid system in the pathophysiology of schizophrenia.

EXCITATORY AND INHIBITORY AMINO ACID NEUROTRANSMITTERS IN THE CONTEXT OF NEURAL CIRCUITRY

The amino acid neurotransmitters are the most abundant and widely used neurotransmitters in the brain. The excitatory neurotransmitter glutamate and the

inhibitory neurotransmitter GABA are the predominant transmitters in both the local and long-range circuits that form distributed neural networks. In the

brain, L-glutamate is synthesized in axon terminals from glucose (via the Krebs cycle) or from glutamine that is converted into glutamate by the enzyme

glutaminase. The synaptic action of glutamate is terminated by the glutamate transporter, which is located on the presynaptic axon terminal. GABA is

synthesized in the brain by the decarboxylation of L-glutamic acid, which is catalyzed by the enzyme glutamic acid decarboxylase. As in other

neurotransmitter systems, the synaptic action of GABA is terminated by the GABA transporter. In the following section, we focus on the cell types and

projections utilizing these two neurotransmitters in the neocortex, basal ganglia, and thalamus, given that these brain regions have been implicated in the

pathophysiology of a number of psychiatric disorders.

Cerebral Cortex

Pyramidal cells, the predominant projection neurons of the cerebral cortex, utilize glutamate as their neurotransmitter. Most pyramidal neurons are

characteristically shaped and possess a single apical dendrite that extends toward the pial surface. In addition, several basilar dendrites extend from the base

of the cell body in a radial fashion. Dendritic spines, short extensions of the dendritic shafts, coat both apical and basilar dendrites. Pyramidal neurons have

principal axons that enter the white matter and project to other cortical regions, as well as axon collaterals that travel either horizontally or vertically within

the gray matter. In all cortical areas, pyramidal cells are located in layers 2–6, and the laminar location of a pyramidal cell often indicates its projectionPrint: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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target. For example, cortically projecting pyramidal neurons are predominantly located in layer 3, whereas striatal- and thalamic-projecting cells reside in

layers 5 and 6, respectively (DeFelipe and Farinas 1992).

Nonpyramidal neurons are the other major class of cortical neuron, and the majority (90%) of these neurons utilize GABA as their neurotransmitter. Also

known as interneurons, the axons of cortical GABA cells arborize within the gray matter and thus do not project out of the cortical region in which they reside.

As many as 12 different subtypes of GABA neurons can be found in the cortex, and these can be distinguished biochemically, electrophysiologically, and

morphologically (Figure 4–8) (Fairen et al. 1984; Krimer et al. 2005; Lund and Lewis 1993). For example, subpopulations of GABA cells can be distinguished

by the presence of certain neuropeptides or calcium-binding proteins (Condé et al. 1994; Gabbott and Bacon 1996). In addition, the organization of the

axonal arbor and synaptic targets of the axon terminals differ greatly across these different subtypes (Lund and Lewis 1993). As depicted in Figure 4–8, the

chandelier class of GABA cell expresses the calcium-binding protein parvalbumin (DeFelipe et al. 1989; Lund and Lewis 1993) and has axon terminals that are

arrayed as distinct vertical structures, termed cartridges (Fairen and Valverde 1980; Goldman-Rakic and Brown 1982). These axon terminals form inhibitory

or symmetric synapses exclusively with the axon initial segments of pyramidal cells (DeFelipe et al. 1985). Parvalbumin-containing basket neurons form

symmetric synapses with the cell bodies and dendrites of pyramidal neurons (Melchitzky et al. 1999; Williams et al. 1992). Parvalbumin-containing neurons

are predominantly located in layers 3 and 4. Martinotti cells contain somatostatin and form symmetric synapses with the tuft dendrites of pyramidal neurons

(Kawaguchi and Kubota 1997; Wang et al. 2004) and, to a lesser extent, with the dendrites of GABA neurons (Melchitzky and Lewis 2008). Double bouquet

neurons have radially oriented axonal arbors and contain either somatostatin and the calcium-binding protein calbindin (DeFelipe 1993) or the

calcium-binding protein calretinin (Condé et al. 1994). The somatostatin- and calbindin-containing double bouquet cells form symmetric synapses with the

distal dendritic shafts and spines of pyramidal neurons. By contrast, the calretinin-containing double bouquet cells form symmetric synapses predominantly

with the dendritic shafts of other GABA neurons (Gonchar and Burkhalter 1999; Meskenaite 1997), although they also target distal dendritic shafts and spines

of pyramidal neurons to a lesser extent (Melchitzky et al. 2005). Calretinin-containing Cajal-Retzius cells reside solely in layer 1 and target the tuft dendrites

of pyramidal neurons. These subpopulations of GABA neurons have differing laminar patterns of distribution (see Figure 4–8). For example, in the prefrontal

cortex, layers deep 3 and 4 have the majority of parvalbumin-containing neurons (Condé et al. 1994; Gabbott and Bacon 1996); layers 2, superficial 3, and 5

have the greatest density of somatostatin-containing neurons (Lewis et al. 1986); and layer 2 has the highest density of calretinin-containing cells (Condé et

1994; Gabbott and Bacon 1996).

FIGURE 4–8. (A) Schematic illustration of synaptic contacts between different subpopulations of GABA neurons and a layer 3 pyramidal neuron in monkey

prefrontal cortex. (B) Film autoradiograms showing signals for parvalbumin (PV), somatostatin (SST), and calretinin (CR) mRNAs in human prefrontal

cortex.Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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(A) The indicated synaptic connections of each subpopulation of GABA neuron are based on previous studies (see text for details).

(B) Note the different laminar distribution of these three subclasses of GABA neurons. GABA = -aminobutyric acid; WM = white matter.

Source. Adapted from Gonzalez-Burgos G, Hashimoto T, Lewis DA: “Inhibition and Timing in Cortical Neural Circuits” (Images in Neuroscience). American Journal of

Multiple lines of evidence show that GABA neurons in monkey prefrontal cortex are involved in working memory tasks. For example, fast-spiking neurons are

active during the delay period of working memory tasks (Wilson et al. 1994), and injection of GABA antagonists into the prefrontal cortex disrupts working

memory (Sawaguchi et al. 1989). Patients with schizophrenia perform poorly on working memory tasks (Weinberger et al. 1986), and postmortem studies

have demonstrated alterations in markers of GABA neurotransmission in the prefrontal cortex of schizophrenic subjects. For example, reduced mRNA for the

67 kiloDalton isoform of glutamic acid decarboxylase, the principal determinant of GABA synthesis, is one of the most consistent findings in postmortem

studies of individuals with schizophrenia (Akbarian and Huang 2006). In addition, mRNA levels of parvalbumin and somatostatin, but not of calretinin, are

reduced in the prefrontal cortex of subjects with schizophrenia (Hashimoto et al. 2003, 2008).

Thalamus

The dorsal thalamus is a heterogeneous structure composed of numerous nuclei that are distinguished on the basis of their location, cytoarchitecture, and

connections with other brain regions. The projection or relay neurons within these nuclei use glutamate as their neurotransmitter and thus provide excitatory

input to their target regions. For example, the axon terminals that project from the thalamus to primary sensory cortices contain glutamate immunoreactivity

and form Gray’s type I synapses (Kharazia and Weinberg 1994).

There are two groups of GABA-containing neurons in the primate thalamus: the interneurons, whose axons and actions are confined within the various dorsal

thalamic nuclei, and the neurons of the reticular nucleus. All of the neurons in the reticular nucleus are GABAergic, and they provide extensive projections to

the nuclei of the dorsal thalamus, the principal and possibly sole target of the reticular nucleus (Steriade et al. 1997). Thus, as in the cortex, the activity of the

long-range excitatory projections from the thalamus is regulated by inhibitory inputs from nearby GABA neurons.

Basal Ganglia

The basal ganglia consist of the striatum (comprising the caudate nucleus, putamen, and nucleus accumbens), the globus pallidus (internal and external

segments), and the substantia nigra pars reticulata. The internal segment of the globus pallidus and the substantia nigra pars reticulata are often grouped

together and are referred to as the output nuclei of the basal ganglia. In contrast to the cortex and thalamus, the projection neurons of the basal ganglia

utilize GABA as a neurotransmitter. For example, the GABA-containing medium spiny neurons of the striatum, which are the principal target of the excitatory

projections from cortical pyramidal cells (Alexander and Crutcher 1990), project to the output nuclei of the basal ganglia (Figure 4–9). These medium spiny

striatal neurons express substance P and dynorphin as well as GABA (Gerfen and Young 1988). The GABA projection neurons of the output nuclei of the basal

ganglia project to the thalamus, where they form inhibitory contacts with thalamic projection neurons. This pathway from the striatum through the output

nuclei of the basal ganglia to the thalamus is known as the “direct” pathway through the basal ganglia, and it results in disinhibition of the thalamus, which in

turn sends a glutamatergic projection back to the cerebral cortex (Alexander and Crutcher 1990). In the “indirect” pathway (see Figure 4–9), GABA- and

enkephalin-containing neurons in the striatum project to the external segment of the globus pallidus (Gerfen and Young 1988), where they target GABA

projection neurons. The axons of these pallidal projection neurons target glutamate-containing cells in the subthalamic nucleus, which then project to GABA

neurons of the output nuclei of the basal ganglia. Similar to the direct pathway, the output nuclei of the basal ganglia send GABAergic projections to the

thalamus. In both the direct and indirect pathways, the cerebral cortex sends glutamatergic projections to the striatum and receives glutamatergic input from

the thalamus, thus forming a corticostriatal circuit (see Figure 4–9). DA released from neurons in the substantia nigra pars compacta appears to facilitate

transmission through the direct pathway, via D1 receptors on the substance P/dynorphin cells, and to inhibit transmission through the indirect pathway, via

D2 receptors on the enkephalin cells (Albin et al. 1989; Gerfen et al. 1990).

FIGURE 4–9. Schematic diagram of basal ganglia circuitry, illustrating the direct and indirect pathways.Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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See text for details. DA = dopamine; DYN = dynorphin; ENK = enkephalin; GABA = -aminobutyric acid; GPe = external globus pallidus; GPi = internal globus pallidus; SNc

= substantia nigra pars compacta; SNr = substantia nigra pars reticulata; SP = substance P; STN = subthalamic nucleus.

Source. Adapted from Parent A, Sato F, Wu Y, et al: “Organization of the Basal Ganglia: The Importance of Axonal Collateralization.” Trends in Neurosciences 23:S20–S27,

The nigrostriatal projection constitutes one of the major inputs to the basal ganglia. The striatum reciprocates and sends projections back to the midbrain DA

neurons (Figure 4–10), forming a striatonigrostriatal circuit. The midbrain DA neurons can be divided into two tiers: the dorsal tier (which includes neurons of

the dorsal substantia nigra pars compacta, the ventral tegmental area, and the retrorubral group) and the ventral tier (composed of the densocellular and cell

column neurons of the substantia nigra pars compacta) (Haber and Fudge 1997). As illustrated in Figure 4–10, there is an inverse dorsal–ventral

topographical organization to the projection from the dorsal and ventral DA neurons to the striatum (Haber 2003). For example, dorsally and medially located

DA neurons project to the ventral and medial parts of the striatum (red and yellow pathways in Figure 4–10), whereas ventrally and laterally located DA

neurons project to the dorsal and lateral parts of the striatum (green and blue pathways in Figure 4–10). Another prominent input to the striatum derives

from the cerebral cortex, and this projection has a topographic organization related to that of the striatonigrostriatal pathway (see Figure 4–10). The orbital

and medial prefrontal cortices project to the ventral striatum, the dorsolateral prefrontal cortex projects to the central striatum, and the premotor and motor

cortices project to the dorsolateral striatum. These topographies create limbic, associative, and motor pathways (red/orange, yellow, and green/blue,

respectively, in Figure 4–10) within the corticostriatalcortical and striatonigrostriatal projections.

FIGURE 4–10. Organization of striatonigralstriatal projections.Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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The organization of functional corticostriatal inputs (red = limbic, green = associative, blue = motor) is illustrated (see text for details). DL-PFC = dorsolateral prefrontal

cortex; IC = internal capsule; OMPFC = orbital and medial prefrontal cortex; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata. VTA = ventral

tegmental area.

Source. Adapted from Haber SN, Fudge JH, McFarland NR. “Striatonigrostriatal Pathways in Primates Form an Ascending Spiral From the Shell to the Dorsolateral Striatum.”

NEUROPEPTIDES

Neuropeptides are generally thought to modulate the effects of classical neurotransmitters and are often collocated with neurotransmitters within neurons.

This section focuses on six neuropeptides that have been implicated in the pathophysiology of psychiatric disorders.

Corticotropin-Releasing Factor

Corticotropin-releasing factor (CRF) is best known as a hormone that is secreted by the hypothalamus and that stimulates adrenocorticotropic hormone

(ACTH) release from the pituitary, which results in the production of cortisol by the adrenal glands. Specifically, CRF is localized to neurons of the

paraventricular nucleus in the hypothalamus, which send axons to the median eminence. CRF-containing cells are also localized to other hypothalamic nuclei,

such as the medial preoptic area and the dorsomedial, arcuate, and mammillary nuclei (DeSouza and Grigoriadis 2002), as well as to the amygdala and bed

nucleus of the stria terminalis (Keller et al. 2006). Besides the median eminence, CRF axons are present in the cerebral cortex, brain stem (including the locus

coeruleus), and spinal cord. To date, two CRF receptors have been identified, CRF1 and CRF2. CRF1 receptors are expressed in the pituitary, cerebral cortex,

hippocampus, amygdala, and medial septum, and CRF2 receptors are localized to the hypothalamic nuclei, lateral septum, and bed nucleus of the stria

terminalis (Keller et al. 2006).

It has been hypothesized that hyperactivity of hypothalamic CRF might underlie the hypercortisolemia and contribute to the symptomatology seen in major

depression (Aborelius et al. 1999). Furthermore, given that both NE and DA have been shown to be involved with stress as well as with depression, the

presence of CRF-containing axons in NE- and DA-containing nuclei provides another mechanism by which CRF can affect stress responses (Austin et al. 1997).

CRF also appears to have effects on cognitive processing. Of interest, CRF is found in GABA-containing cells in the cerebral cortex, with the highest densities

of these cells found in prefrontal, insular, and cingulate cortices (DeSouza and Grigoriadis 2002). In addition, cortical CRF has also been implicated in major

depression and in Alzheimer’s disease. For example, a decrease in CRF binding sites in the frontal cortex of suicide victims compared with normal controls has

been demonstrated (Mitchell 1998). Furthermore, in postmortem tissue from individuals with Alzheimer’s disease, CRF-containing axons are associated with

amyloid deposits in the cerebral cortex (Powers et al. 1987); reduced CRF levels in frontal, temporal, and parietal cortices are correlated with the severity of

dementia (Davis et al. 1999).

Neuropeptide Y

Neuropeptide Y (NPY) is a 36–amino acid peptide that, along with its receptors, is widely distributed within the central nervous system (Wettstein et al.

1995). The regions of the human brain that contain high densities of NPY-containing neurons include the striatum and amygdala, with the hypothalamus,

cerebral cortex, hippocampus, periaqueductal gray, and basal forebrain having moderate levels of NPY-containing cells (Schwartzberg et al. 1990). Five G

protein–coupled NPY receptor subtypes, termed Y1–Y5, have been identified and cloned (Redrobe et al. 2002). The NPY receptors Y1 and Y2 are the most

abundant and are found in the cerebral cortex, thalamus, brain stem, and hypothalamus (Redrobe et al. 2002). In addition to its role in regulating eating

behavior, NPY has been implicated in affective disorders. For example, in a rodent model of depression, chronic antidepressant treatment increased NPY and

Y1 mRNA levels (Caberlotto et al. 1998). In humans, cerebrospinal fluid and plasma levels of NPY are lower in depressed patients than in controls (Nilsson et

1996; Westrin et al. 1999), and these levels increase after electroconvulsive therapy (Mathé et al. 1996). In addition, NPY mRNA is reduced in the

prefrontal cortex of subjects with bipolar disorder (Caberlotto and Hurd 2001) and subjects with schizophrenia (Hashimoto et al. 2008).

Substance PPrint: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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Substance P is a member of the family of neuropeptides known as the tachykinins, which also includes neurokinin A and B. The actions of these neuropeptides

are mediated through the specific G protein–coupled receptors NK1, NK2, and NK3, and substance P is the preferred agonist for the NK1 receptor (Hökfelt et

2001). Substance P is found throughout the nervous system. In particular, substance P is expressed in brain regions that appear to be involved in emotion,

such as the amygdala, periaqueductal gray, and hypothalamus (Pioro et al. 1990). In addition, substance P is collocated with serotonin in approximately 50%

of the dorsal raphe neurons in the human brain (Baker et al. 1991; Sergeyev et al. 1999), and a large number of serotonin-containing dorsal raphe neurons

express the NK1 receptor (Lacoste et al. 2006).

Studies in animals have suggested that substance P, besides having a role in pain and inflammation, may also be involved in anxiety and in neurochemical

responses to stress. For example, injection of substance P into periaqueductal gray matter produced anxiety-like behavior in rats (Aguiar and Brandao 1996).

Furthermore, in guinea pigs subjected to maternal separation, the number of neurons with NK1 receptor internalization increased in the basolateral amygdala

(Kramer et al. 1998).

Substance P also appears to be involved in depression. For example, elevated concentrations of substance P have been reported in the cerebrospinal fluid of

depressed patients (Rimon et al. 2002).

Neurotensin

Neurotensin is a tridecapeptide found throughout the brain, with high tissue concentrations in the amygdala, lateral septum, bed nucleus of the stria

terminalis, substantia nigra, and ventral tegmental area (Caceda et al. 2006). Similarly, neurotensin-immunoreactive neurons are found in the amygdala, bed

nucleus of the stria terminalis, lateral septum, and preoptic and lateral hypothalamus (Geisler et al. 2006). Three types of neurotensin receptors have been

cloned, NTS1–NTS3, with NTS1 and NTS2 being G protein–coupled receptors and NTS3 belonging to the vacuolar sorting receptor family (Caceda et al. 2006).

High levels of mRNA for all three of these receptor types are found in the substantia nigra and amygdala.

Neurotensin has a strong association with the dopaminergic system, as evidenced by the heavy neurotensin innervation of nuclei that have high densities of

DA cells or axons, such as the ventral tegmental area and the amygdala, respectively (Geisler et al. 2006). In addition, the majority of DA neurons in the

ventral tegmental area express NTS1 (Fassio et al. 2000), and neurotensin axons in this area arise from the preoptic and lateral hypothalamus (Zahm et al.

2001). Because of the role of DA in neuropsychiatric disorders such as schizophrenia, the localization and function of neurotensin in the brain have been

widely studied. One of the most consistent findings is reduced cerebrospinal fluid concentrations of neurotensin in neuroleptic-naive people diagnosed with

schizophrenia (Sharma et al. 1997). In addition, clinically effective antipsychotic drug treatment may increase cerebrospinal fluid neurotensin levels in

schizophrenia (Sharma et al. 1997). Neurotensin has also been implicated in Parkinson’s disease, which involves the progressive loss of DA neurons in the

striatum. For example, decreases in neurotensin receptor binding as well as in NTS1 receptor mRNA have been found in the substantia nigra and striatum of

patients with Parkinson’s disease (Yamada et al. 1995).

Somatostatin

The neuropeptide somatostatin was first identified in the hypothalamus as a tetradecapeptide (Brazeau et al. 1973). Other peptides of the somatostatin

family, all of which are derived from the prosomatostatin protein, include somatostatin-28 and somatostatin-281–12 (Benoit et al. 1982). The hypothalamus

and limbic regions such as the amygdala and hippocampus have large numbers of somatostatin-containing neurons. A small number of somatostatin neurons

are localized to the cerebral cortex and are particularly abundant in layers 2–3 and layers 5–6 (Epelbaum et al. 1994). Somatostatin-containing neurons in the

cerebral cortex have a nonpyramidal morphology and contain GABA (Hendry et al. 1984). The principal somatostatinergic tract projects from the anterior

periventricular nucleus of the hypothalamus to the median eminence (Patel 1999). This projection inhibits secretion of growth hormone, thyroid-stimulating

hormone, and prolactin from the adenohypophysis (Epelbaum et al. 1994). The actions of somatostatin are mediated by five distinct subtypes of G

protein–coupled receptors, SST1–SST5. The SST2 receptor undergoes alternative splicing that results in two forms, SST2A and SST2B (Epelbaum et al. 1994).

Although all somatostatin receptors appear to be present in the brain (Patel 1999), the SST2 receptor is the most widely studied. In rodent brain, the SST2A

receptor protein has been localized to the cerebral cortex, basal ganglia, and hippocampus (Dournaud et al. 1996; Hervieu and Emson 1998).

The widespread distribution of somatostatin cells and receptors reflects the varied physiological actions that somatostatin release has in the nervous system,

ranging from thermoregulation to cognitive functions such as learning and memory (Epelbaum et al. 1994). Deficits in the somatostatin system in Alzheimer’s

disease are some of the most consistent findings in this neurodegenerative disease. Decreases in cerebrospinal fluid somatostatin levels, selective

degeneration of cortical somatostatin neurons, and reduction in cortical somatostatin receptors have all been found in Alzheimer’s disease (Bissette 1997).

Somatostatin has also been implicated in the pathophysiology of schizophrenia. For example, studies have revealed decreased expression of somatostatin

mRNA in the prefrontal cortex of individuals with schizophrenia (Hashimoto et al. 2008), specifically in layers 2–6 (Morris et al. 2008).

Orexins

The orexin neuropeptides, orexin A and orexin B (also known as hypocretin A and hypocretin B), were identified in the late 1990s as endogenous ligands for

two orphan G protein–coupled receptors (de Lecea et al. 1998; Sakurai et al. 1998). Orexin A and orexin B are derived from a single precursor gene,

prepro-orexin. Because neurons in the lateral hypothalamic area, a region with an established role in feeding behavior, produce these neuropeptides, Sakurai

et al. (1998) named them orexins, based on the Greek word for appetite, orexis. Neurons producing orexin are also located in posterior and perifornical

hypothalamus. Estimates of the number of orexin neurons range from 3,000 in rat brain (Nambu et al. 1999) to 7,000 in human brain (Peyron et al. 1998).

Orexin neurons project throughout the brain, with the exception of the cerebellum (Figure 4–11). Interestingly, orexin neurons project to most of the

monoaminergic (substantia nigra, locus coeruleus, dorsal raphe) and cholinergic (medial septum, pedunculopontine, laterodorsal tegmental) nuclei (Sakurai

2007). Orexin neurons also have widespread projections throughout the cerebral cortex. Areas containing high densities of orexin axons include the

paraventricular thalamic nucleus, the arcuate nucleus of the hypothalamus, the locus coeruleus, and the dorsal raphe nucleus (Nambu et al. 1999).

FIGURE 4–11. Projections of orexin-containing neurons in the human brain.Print: Chapter 4. Chemical Neuroanatomy of the Primate Brain http://www.psychiatryonline.com/popup.aspx?aID=416627&print=yes…

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SN = substantia nigra; VTA = ventral tegmental area.

Source. Adapted from Heimer 1995.

The multiple actions of orexin are mediated by two types of G protein–coupled receptors, orexin 1 and orexin 2, which display high homology. In concert with

the widespread projections of orexin neurons, the orexin receptors are located throughout the brain (Marcus et al. 2001). For example, the mRNA for orexin 1

is found in the prefrontal cortex, the CA2 field of the hippocampus, the paraventricular thalamic nucleus, the ventromedial hypothalamic nucleus, and the

locus coeruleus. The distribution of the mRNA for orexin 2 is somewhat complementary to that of orexin 1 in that it is found in the piriform cortex, CA3 field of

the hippocampus, rhomboid thalamic nucleus, dorsomedial hypothalamic nucleus, and tuberomammillary nucleus (Marcus et al. 2001). Some regions of the

brain, such as the raphe nuclei, ventral tegmental area, and substantia nigra, express both orexin receptors.

The location of orexin-containing neurons in the feeding center of the brain (lateral hypothalamic area) and the projections of orexin neurons to neuronal

systems involved in sleep and wakefulness (locus coeruleus, raphe nuclei, and laterodorsal/pedunculopontine tegmental nuclei) and reward (ventral

tegmental area) illustrate the variety of functions in which orexin neurons participate (Harris and Aston-Jones 2006). Supporting orexin’s involvement in

feeding behavior, administration of an anti-orexin antibody or an orexin 1 receptor antagonist to rats reduces food intake (Haynes et al. 2002; Yamada et al.

2000). Numerous studies in both animals and humans show that orexin deficiency is the main cause of narcolepsy. For example, mice that lack the orexin

gene exhibit physiological symptoms similar to those of human narcolepsy (Chemelli et al. 1999). More direct evidence of orexin’s role in narcolepsy is that

postmortem examination of the brains of narcolepsy patients revealed an 85%–95% reduction in the number of orexin-immunoreactive neurons (Thannickal

et al. 2000). A recent study of an orexin receptor antagonist demonstrated the usefulness of this drug in inducing sleep without cataplexy (Brisbare-Roch et

2007), providing hope to people who suffer from sleeping disorders like narcolepsy. Current treatments for narcolepsy include addictive amphetamine-like

drugs, but patients taking these drugs rarely become addicted (Harris and Aston-Jones 2006). This finding has led to speculation that orexins may also be

involved in reward processing and addiction. For example, orexin neurons activate ventral tegmental DA neurons, which, through their projections to the

nucleus accumbens, form the “reward” pathway. In addition, in rodents, administration of orexin directly into the ventral tegmental area reinstates an

extinguished drug preference (Harris et al. 2005).

CONCLUSION

This chapter reviews the basic framework of the anatomical distribution of the major neurochemical systems in the primate brain, including the anatomical

determinants of where neurotransmitters are released and where they produce their effects. These organizational schema provide important constraints on

the actions of the neurotransmitters and neuromodulators. In addition, the consequences of the cellular actions and of pharmacological manipulations of their

synthesis, release, reuptake, and receptor binding depend on the rich and diverse interplay across these neurochemical systems. Clearly, a major challenge

for the future involves the elucidation of these interactions and the characterization of how these interactions are disturbed in psychiatric disorders. Such

information is critical for identification and validation of potential molecular targets for the rational development of new pharmacotherapies for psychiatric

illnesses.

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Course Content

Introduction to Primate Neuroanatomy

Basics of Primate Neuroanatomy
Comparative Anatomy of the Primate Brain
Neuroanatomical Techniques in Primatology
Quiz on Primate Brain Structures
Functional Aspects of Primate Brain Regions

Mapping the Primate Brain: Structure and Function

Neurotransmitters and Their Roles in Primate Behavior

Comparative Analysis of Primate Brain Chemistry

Concluding Insights on Primate Neuroanatomy and Chemistry

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Chapter 4 Chemical Neuroanatomy of the Primate Brain

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Course Content

Introduction to Primate Neuroanatomy

Basics of Primate Neuroanatomy

Comparative Anatomy of the Primate Brain

Neuroanatomical Techniques in Primatology

Quiz on Primate Brain Structures

Functional Aspects of Primate Brain Regions

Mapping the Primate Brain: Structure and Function

Introduction to Primate Neuroanatomy

The Role of the Prefrontal Cortex in Primates

Comparative Analysis of Primate Brain Structures

Neuroanatomy Structure Identification Quiz

Functional Mapping Techniques in Primate Research

Neurotransmitters and Their Roles in Primate Behavior

Introduction to Neurotransmitters

Dopamine: The Reward Pathway and Beyond

Serotonin and Mood Regulation in Primates

Assessing Knowledge on Neurotransmitter Functions

Norepinephrine: Attention and Arousal Mechanisms

Comparative Analysis of Primate Brain Chemistry

Introduction to Primate Neuroanatomy

Chemical Signaling in Primate Brains

Neuroanatomical Structures and Their Functions

Quiz on Primate Neuroanatomy and Chemistry

Comparative Study of Neurotransmitter Systems

Concluding Insights on Primate Neuroanatomy and Chemistry

Integration of Neuroanatomy and Neurochemistry in Primates

Comparative Analysis of Primate Brain Structures

Assessment on Primate Neuroanatomy and Chemistry

The Evolutionary Significance of Neurochemical Diversity

Synthesis of Primate Brain Research Findings

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