Neuroanatomy Of The Dopamine System

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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.

Anatomia Emocjonalna

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 7-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.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

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 Ultrastructural Localization." Journal of Comparative Neurology 432:119-138, 2001. Copyright 2001, Wiley. Used with permission.

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 L -hydroxylase-, (C) choline acetyltransferase-, and (D) serotonin-immunoreactive axons in area 9 of macaque monkey prefrontal cortex.

FIGURE 4-3. Darkfield photomicrographs of (A) tyrosine hydroxylase-, (B) dopamine L -hydroxylase-, (C) choline acetyltransferase-, and (D) serotonin-immunoreactive axons in area 9 of macaque monkey prefrontal cortex.

Copyright © American Psychiatric Publishing, Inc., ok American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

Note the differences in relative density and the distinctive laminar distribution of each afferent system. Scale bar = 200 Um. 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.

Dopamine Norepinephrine

FIGURE 4-4. Schematic representation of coronal sections from macaque monkey prefrontal cortex illustrating the relative densities of dopamine, norepinephrine, serotonin, and acetylcholine axons.

Serotonin Acetylcholine

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

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). 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 (And reasen 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 13-hydroxylase (DBH).

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 13-hydroxylase (DBH).

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

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 Um. 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 103:1033-1042, 2001. Copyright 2001, Elsevier. Used with permission.

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.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

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 Um.

Source. Reprinted from Melchitzky DS, Lewis DA: "Tyrosine Hydroxylase- and Dopamine Transporter-Immunoreactive Axons in the Primate Cerebellum: Evidence for a Lobular- and Laminar-Specific Dopamine Innervation." Neuropsychopharmacology 22:466-472, 2000. Copyright 2000, Elsevier. Used with permission.

Receptors

Five genes encoding five unique DA receptors have been identified. All of these receptors belong to the superfamily of seven-transmembrane-domain G 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 Di and D2 subtypes. The Di receptor subtype includes the Di 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 Di receptor, although the Di receptor is more prevalent (described in detail later in this section) (Meador-Woodruff i994). 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. Di 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. 200i; Jaber et al. i996; Meador-Woodruff et al. i996). In the cerebellum, Di receptor mRNA is expressed in the anterior lobules within the granular cell layer (Mengod et al. i99i). Di receptor mRNA is found in all layers of the cerebral cortex, but cortical regions exhibit different laminar patterns (Meador-Woodruff et al. i99i). Brain regions that do not contain Di receptor mRNA include the substantia nigra pars compacta and the ventral tegmental area (Meador-Woodruff i994). In addition, the Di 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. i995). In these regions, the Di receptor is predominantly located postsynaptically in dendritic spines. The Di receptor protein has also been localized to the medium-sized GABA neurons in the caudate nucleus (Bergson et al. i995). A positron emission tomography study revealed an increase in the binding of NNCii2, a Di receptor ligand, in drug-free and drug-naive schizophrenia patients, consistent with a compensatory Di 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 Di receptor mRNA include the substantia nigra pars compacta and the ventral tegmental area (Hurd et al. 200i; Meador-Woodruff i994).

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. 200i; Jaber et al. i996; Meador-Woodruff et al. i996). 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. i996; Meador-Woodruff i994). 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. i992) and also express the D2 receptor protein (Khan et al. i998). Limbic regions of the brain, such as the nucleus accumbens, have the highest density of D3 receptor mRNA in the brain (Jaber et al. i996; Meador-Woodruff i994). 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 i0 of the cerebellar vermis express the D3, as well as the D2, receptor mRNA (Diaz et al. i995; Mengod et al. i992).

The D4 and D5 receptor mRNAs are not as highly expressed in the brain as are the mRNAs for the Di-D3 receptors (Jaber et al. i996; Meador-Woodruff i994). 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. i996). 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. i996; Meador-Woodruff i994). 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. i995).

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