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Dopaminergic Innervation of the Monkey Caudal Nucleus Accumbens
Brain Research Bulletin, Vol. 43, No. 4, pp. 417–423, 1997 Copyright q 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0361-9230/97 $17.00 / .00
PII S0361-9230(97)00028-2
Dopaminergic Innervation of the Monkey Caudal Nucleus Accumbens KEIKO IKEMOTO1 Department of Psychiatry, Shiga University of Medical Science, Seta Tsukinowacho, Otsu, 520-21, Japan [Received 27 August 1996; Accepted 16 December 1996] ABSTRACT: Previous studies have shown that the monkey (Macaca fuscata) caudal nucleus accumbens is neurochemically subdivided into three subdivisions, the medial, dorsolateral, and ventral subdivisions. In this study, dopaminergic innervation of these three subdivisions was studied in detail for the first time by light microscopic immunocytochemistry using a monoclonal antibody against dopamine. The patterns of dopamine fiber distribution were heterogeneous even within each subdivision. The medial subdivision showed extremely dense accumulation of thick dopamine-immunoreactive varicose fibers. Some areas with densely packed cells in Nissl-stained sections corresponded to dopamine-poor areas, while another area with concentrated cells corresponded to a dopamine-rich area. There were also areas with sparse cells that contained a few dopamine-immunoreactive fibers. In the dorsolateral subdivision thick dopamine-immunoreactive varicose fibers were found sparsely among diffuse puncta. The ventral subdivision exhibited similar profiles to those in the dorsolateral one, and there were also many characteristic spiral dopamine-immunoreactive fibers of passage. The present study indicates that the dopaminergic structures of the monkey nucleus accumbens differ according to the subterritories, and are morphologically different from those in the caudate-putamen. Q 1997 Elsevier Science Inc.
three subterritories have been demonstrated to have different afferent and efferent projections in the rat (for review, see [10]). Our recent study has demonstrated that the monkey NAC is more complicated than as has been considered, and the caudal part can be subdivided into three subterritories, i.e., medial, dorsolateral, and ventral subdivisions . The dorsolateral subdivision apparently corresponds to the rat core, and both the medial and ventral subdivisions appear to correspond to the rat shell, based on SP and CBD immunoreactivities. The medial subdivision is rich in DA- and neuropeptide (SP and neurotensin) immunoreactive (IR) fibers, whereas the ventral subdivision shows lower densities of DA- and neuropeptide (SP, neurotensin, and enkephalin) IR fibers [13]. It has been demonstrated that DA modulates the synaptic responses distinctly between subdivisions of the NAC [26], and DA depletion or blockage affect the accumbal subdivisions differentially in the rat [3,23,24]. In the monkey NAC, the distribution of D2 blocker-sensitive neurons differed between the subdivisions [13]. Such a functional heterogeneity of DA should be based on the heterogeneity of DA innervation in the NAC. The previous study using DA antibody revealed that monkey NAC medial subdivision possesses extremely dense DA fibers. In addition, unlike the dorsal striatum, the primate NAC receives considerable amounts of noradrenergic fibers [6,30] compared with rodents [27]. Indeed, the study using a noradrenaline antibody revealed many noradrenaline-IR fibers in the dorsomedial region of the monkey NAC [15]. Therefore, it is essential to use the DA antibody, but not the antibody against tyrosine hydroxylase, the synthesizing enzyme of DA, as well as noradrenaline to study the morphological characteristics of DA structures in the NAC of higher mammalian species. The present study was conducted to clarify detailed morphological characteristics of DA-containing structures in the caudal three subterritories of the monkey NAC by employing a DAmonoclonal antibody [7].
KEY WORDS: Immunocytochemistry, Dopamine, Medial subdivision, Dorsolateral subdivision, Ventral subdivision.
INTRODUCTION The nucleus accumbens (NAC) is heavily innervated by midbrain dopaminergic neurons, and is thought to regulate motivated state of behavior. The NAC has been proposed to be involved in the pathogenesis of schizophrenia [1,18] and in the therapeutic action of antipsychotic drugs [23,28]. In the schizophrenic brain, a higher dopamine (DA) content and an increase of dopamine D2 receptors have been reported [1,17–19]. Recent studies have described that the primate NAC is a distinct anatomical territory within the ventral striatum [13,21,22, 25]. The compartmental organization of the NAC is different from that of the striatum, which can be divided into patch and matrix regions [8,38]. According to the recent reviews, the rat NAC can be divided into three subterritories, i.e., shell, core, and rostral pole [38,39]. The core exhibits moderate substance-P (SP) and high calbindin D28 (CBD) immunoreactivities, while the shell shows high SP and moderate CBD immunoreactivities [34,37]. In the core medium-sized cells are packed [36]. These 1
MATERIALS AND METHODS Animals Five adult Japanese monkeys, Macaca fuscata, of both sexes weighing 6–9 kg, were used. The animals were housed and fed for several months in the Institute for Experimental Animals, in Shiga University of Medical Science.
Present address: Department of Anatomy, Fujita Health University, School of Medicine, Toyoake, Aichi, 470-11, Japan.
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Immunocytochemistry Each monkey was deeply anesthetized with ketamine hydrochloride (Ketalar, Sankyo, 25 mg/kg, IM) and sodium pentobarbital (Nembutal, Dainippon Pharm., 10 mg/kg, IV), and perfused through the ascending and descending aorta with 1 liter of 1% sodium pyrosulfite (MBS) in 0.01 M phosphate buffer saline (pH 7.4), followed by the fixative described by Van Eden et al. [32] containing 5% glutaraldehyde (GA) and 1% MBS (pH 7.5). After perfusion for 30 min, the brain was removed from the cranium and cut into 4 mm-thick blocks, followed by postfixation in the solution containing 2% GA and 1% MBS for 3 h. The blocks were then stored in a 0.1 M phosphate buffer (PB) solution containing 15% sucrose, 1% MBS, and 0.1% sodium azide at 47C (pH 7.4). More than 3 weeks later, 30 or 50 mmthick coronal sections were cut using a cryostat [13,14,20]. These sections were stored in the same PB–sucrose–MBS solution. The sections were rinsed in 0.3% Triton X-100 in phosphate buffer saline (0.1 M PBS, pH 7.4, 0.9% NaCl ) for at least 3 days before processing for DA immunohistochemistry. The brain sections were incubated in a primary antibody against DA [7] (dilution of 1:10, 000) for 1 week at 47C, then treated by biotinylated goat antimouse IgG (Vector, diluted 1:1,000 ), followed by the ABC method [12], and finally reacted with 3,3 *diaminobenzidine–hydrogen peroxide solution containing 1% nickel ammonium sulfate [31]. After immunostaining, the sections were mounted onto gelatin-coated glass slides and some were counterstained with neutral red or cresylecht violet. The specificity of immunoreactivity was examined by absorption test. No immunoreactivity was observed. RESULTS Dopamine-IR fibers were observed throughout the NAC. In general, the pattern of distribution of DA-IR fibers was more heterogenous than that in the caudate nucleus and putamen ( Fig. 1 ) . The Medial Subdivision Dopamine-IR fibers were extremely dense in the medial subdivision of the NAC. In most animals, the quantity of DA-IR fibers was the highest in the medial subdivision. In some cases, the marginal area between the dorsolateral and ventral subdivisions showed as many fibers as the medial subdivision (Fig. 1). The delineation between the medial subdivision and the caudate nucleus was readily descernible by not only the EP-line, a linear structure extending from the ventral aspect of the lateral ventricle toward the dorsolateral part of the nucleus [13] (Figs. 1 and 3A and B, thick arrows), but also DA immunoreactivity. Because the medial subdivision contained more DA-IR fibers than the caudate nucleus (Figs. 1, 2B, and 3A). In high-power magnification, a characteristic dense accumulation of DA varicose fibers were observed in this subdivision (Fig. 2A). These fibers were different in shape from those in the dorsolateral subdivision and caudate nucleus (Figs. 2A, C, and D, and 4A–C). As shown in Fig. 3C and D, the medial subdivision was composed of heterogenous compartments with respect to DA content and cytoarchitecture. Although the pattern of distribution of dopaminergic fibers varied according to the compartments within the medial subdivision, quantity of DA fibers did not correlate with the degree of cell concentration. Some areas with densely packed cells in Nissl-stained sections corresponded to DA-poor areas (Fig. 3C and D arrows), while another area with concentrated cells corresponded to a DA-rich area (area ‘‘a’’ of Fig. 3C
FIG. 1. Dopamine (DA)-immunostained section of the caudal nucleus accumbens of the macaque monkey. In the nucleus accumbens (NAC), the distribution of DA-immunoreactive (IR) fibers is more heterogenous compared with that in the caudate nucleus (cn). In the dorsal NAC, the delineation between the caudate nucleus is clear by DA immunoreactivity. The ventromedial margin of the NAC is obscure in the DA immunostained sections. The medial subdivision (M) is most heavily innervated by DA-IR fibers. A part of the dorsolateral subdivision (DL) contains low to moderate quantity of DA-IR fibers. The marginal area of the three subdivision is also intensely DA-IR. Dopamine immunoreactivity of the ventral subdivision (V) is partly low to moderate. Arrow indicates EP-line [13]. The sections are 50-mm thick. Bar Å 1 mm. ic, internal capsule; mC, major island of Calleja; OT, olfactory tubercle; S, septum; ve, lateral ventricle; VP, ventral pallidum.
and D). There were also areas with sparse cells that contained a few DA-IR fibers (area ‘‘b’’ of Fig. 3C and D). Some of the animals showed DA-IR thick varicose fibers and diffuse puncta in the dense DA-IR field, which were similar to those in the dorsolateral subdivision. The distribution pattern differed between the animals. The Dorsolateral Subdivision Low to moderate amount of DA-IR thick varicose fibers were sparsely observed among diffuse DA-IR puncta in the dorsolateral subdivision (Fig. 2B). The varicose fibers were generally more thick than those in the caudate nucleus (Figs. 2B and C and 4B and C). A part of the dorsolateral subdivision showed a dense DA-IR fiber plexus that was similar to those in the medial subdivision (Fig. 2C, arrows), a part of which invaded into the ventral subdivision (Fig. 1).
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FIG. 2. Dopamine-containing fibers in the macaque NAC. The sections are 30-mm thick. Bars Å 100 mm. ( A ) Characteristic dense accumulation of DA-IR varicose fibers in the medial subdivision. ( B ) The dorsal border of the dorsolateral subdivision ( DL ) with the caudate nucleus ( cn ) and the medial border with the medial subdivision ( M ) ( arrows ) . The dorsolateral subdivision ( DL ) possesses less varicose fibers than the medial subdivision ( M ) . ( C ) Thick DA-IR varicose fibers in the dorsolateral subdivision. DA-IR fibers are scattered within diffuse puncta. A part of the dorsolateral subdivision shows a dense DA-IR fiber plexus as observed in the medial subdivision ( arrows ) . ( D ) The caudate nucleus contains fine DA-IR varicose fibers and a few thick DA-IR fibers among the moderately stained numerous diffuse puncta, which are different from the DAIR structures of any subdivision of the NAC.
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FIG. 3. (A,B) Two adjacent sections through dorsal NAC. Dopamine-immunostained section (A) and Nissl-stained section (B). The sections are 30-mm- thick. EP-line [13] is the linear structure that consists of darkly Nissl-stained cells extending from the ventral aspect of the lateral ventricle (ve) into the center of the dorsolateral subdivision (DL). It serves as an anatomical landmark to distinguish the medial subdivision (M) from the caudate nucleus (cn). Note the compactly arranged medium-sized cells in the dorsolateral subdivision (DL) (area surrounded by arrows), which correspond to the rat core. The DA immunoreactivity is the highest in the medial subdivision (M), and less in the dorsal area of the dorsolateral subdivision (DL). Bars Å 1 mm. (C,D) Two adjacent sections throughout the medial subdivision in which the heterogeneity of DA immunoreactivity is conspicuous. The sections are 50-mm thick. White broken lines served as to delineate the DA-rich and DA-poor areas (C). Corresponding areas were delineated by black broken lines on the photomicrograph of the adjacent sections stained with cresylecht violet (D). Areas with densely packed cells in Nissl-stained sections correspond to DA-poor islands (arrows), while another area with concentrated cells correspond to DA-rich area (area ‘‘a’’). There are also areas with sparse cells that contain a few DA-IR fibers (area ‘‘b’’). Dopamine intensity does not correlate with the degree of cell concentrations. Bars Å 200 mm. mC, major island of Calleja.
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FIG. 4. High-power photomicrographs of DA-positive fibers. The sections are 30-mm thick. Bars Å 20 mm. (A) Dense DA-IR fiber plexus in the medial subdivision. (B) Dopamine-IR thick varicose fibers in the dorsolateral subdivision. (C) Dopamine-IR fibers in the caudate nucleus. Many of them are more fine than those in the NAC dorsolateral subdivision.
FIG. 5. Dopamine-containing structures in the ventral subdivision of the macaque NAC. The sections are 30-mm thick. (A) Irregularly arranged DA-IR varicose fibers and characteristic thick spiral fibers of passage (arrows) are observed within diffuse puncta in the ventral subdivision. Bar Å 75 mm. (B) Some of the DA-IR fibers of passage form bundles of five to six fibers within the non-DA-IR fiber bundles (arrows) at the middle and caudal levels of the ventral NAC. Bar Å 100 mm.
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The Ventral Subdivision In the ventral subdivision, the density of DA-IR fibers was mostly low to moderate. But some areas were noted for exceptionally high concentration of DA fibers (Fig. 1), of which distribution varied between individual animals. Irregularly arranged DA-IR varicose fibers were distributed within the ventral subdivision (Fig. 5A and B). The characteristic structures of the ventral subdivision were thick DA-IR fibers of passage that occasionally ran spirally (Fig. 5A, arrows). Some of these DA fibers formed bundles of five to six fibers within the non-DA-IR fiber bundles at middle and caudal levels of the NAC (Fig. 5B, arrows). The boundary between the ventral subdivision and the medial one was obscure in DA immunostained sections (Fig. 1). The dorsolateral border of the NAC with the putamen was also unclear. DISCUSSION This is the first study that detailed the heterogeneity in forms and densities of DA-IR fibers in the three subdivisions of the caudal NAC, i.e., medial, dorsolateral, and ventral subdivisions. The characteristics of DA-IR structures in each NAC subdivision differed markedly, and the patterns of DA fiber distribution were not homogenous even within themselves. Such a heterogeneity in the NAC was more conspicuous in the caudal area than in the rostral area. This finding is in accordance with previous reports in the rat [9,33,34,38]. The present study demonstrated that the medial subdivision possesses a unique DA-positive fiber plexus, which is morphologically distinct from the other two caudal subdivisions and caudate nucleus. An ultrastructural study using the same DA antibody demonstrated that DA-IR terminals in the medial subdivision are large sized (0.33 { 0.27 mm) [14] in comparison with those reported in the monkey striatum using an antibody against tyrosine hydroxylase [29]. In the synaptology, there are more asymmetric junctions of the DA-IR terminals in the medial subdivision than the striatum [14,29]. It was supposed that wiring DA transmission, but not the volume DA transmission [5] predominates in the medial subdivision than in the striatum [14]. The present results provided another evidence showing clear morphological differences between the caudate nucleus and the NAC medial subdivision in the monkey. Our previous study has shown that c- fos expression induced by the DA-blocker haloperidol is enhanced in the NAC, especially in the medial subdivision. This subdivision is rich in neuropeptides and noradrenaline as well as DA [13,15]. Martin et al. [22] demonstrated that glutamate receptors, GluR1 are abundant in the medial subdivision, and ultrastructurally, GluR1-IR dendritic shaft and dendritic spine form asymmetric synapses. At present, precise interaction between DA and glutamate in this area is not clear. In the rat neocortex, DA is thought to inhibit the actions of glutamate in synaptic complex [16]. Among the monkey NAC three subdivisions [13,15], the medial subdivision is likely to correlate most deeply with actions of antipsychotics. This subdivision is recognized to be a putative homologous area of the rat dorsal shell. Interestingly, the rat dorsal shell has not only dense fiber connections between the limbic brain [9,10,35], but also many corticotropin-releasing factor receptors [2]. In addition, the rat shell is also shown to be an acting site of various antipsychotics (for review, see [4]). The previous studies using this DA antibody have shown that ‘‘cone-shaped area’’ in the rat medial NAC is heavily innervated by DA-IR fibers [33,34]. The ‘‘cone-shaped area’’ is reported to be capped by the DA-poor area in the rat NAC [33]. In the
medial subdivision of the monkey NAC, we could not find such DA-poor area dorsal to the DA-rich area. It is clearly a species difference. The correlation between the cell concentration and the DA innervation in rat NAC have been discussed previously [11,33]. For example, Herkenham et al. [11] reported that DA fluorescence is weak in the cell cluster, supporting the idea that the projections from dopaminergic cells in the ventral tegmental area avoid cell clusters. On the other hand, the report of Voorn et al. [33] described that the areas with high DA immunoreactivity avoid areas with dense cell populations on one hand and coincide with the cell-dense area in another. In agreement with Voorn et al., the present study showed that the correlation between the quantity of the DA-IR fibers and the degree of cell concentration was inconsistent in the medial subdivision (Fig. 3C and D). In this study, the dorsolateral subdivision was shown to have somewhat the characteristics of the striatum in DA morphology compared with the other subdivisions. But, the thickness of DAIR fibers was generally more large in the dorsolateral subdivision than in the caudate nucleus. The functions of monkey NAC dorsolateral subdivision are not yet clear. The ventral subdivision exhibited mostly similar profile to DA-containing structures of dorsolateral subdivision. However, in the present study, the characteristic DA-containing structures were demonstrated to be thick spiral fibers of passage in the ventral subdivision. Electron-microscopical studies would clarify further morphological characteristics. At present, being different from the rodent NAC, studies of functional heterogeneity in the primate NAC are very few. In this study, functional aspects of the monkey NAC medial subdivision were discussed. Further studies should be conducted to elucidate the role in the etiology of psychosis and therapeutic actions of this unique cell group in the ventral striatum. ACKNOWLEDGEMENTS
The author thanks to Dr. Geffard (Laboratoire d’Immunologie, Universite´ de Bordeaux II) for providing the antibody against dopamine, Dr. Maeda (Department of Anatomy, Shiga University of Medical Science), Dr. Satoh (Department of Psychiatry, Shiga University of Medical Science), and Dr. Kitahama (De´partement de Me´decine Expe´rimentale, Universite´ Claude Bernard) for their helpful suggestions. This study was supported by Grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture in Japan (B-02454292, C-06670959).
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Dopaminergic Innervation of the Monkey Caudal Nucleus Accumbens KEIKO IKEMOTO1 Department of Psychiatry, Shiga University of Medical Science, Seta Tsukinowacho, Otsu, 520-21, Japan [Received 27 August 1996; Accepted 16 December 1996] ABSTRACT: Previous studies have shown that the monkey (Macaca fuscata) caudal nucleus accumbens is neurochemically subdivided into three subdivisions, the medial, dorsolateral, and ventral subdivisions. In this study, dopaminergic innervation of these three subdivisions was studied in detail for the first time by light microscopic immunocytochemistry using a monoclonal antibody against dopamine. The patterns of dopamine fiber distribution were heterogeneous even within each subdivision. The medial subdivision showed extremely dense accumulation of thick dopamine-immunoreactive varicose fibers. Some areas with densely packed cells in Nissl-stained sections corresponded to dopamine-poor areas, while another area with concentrated cells corresponded to a dopamine-rich area. There were also areas with sparse cells that contained a few dopamine-immunoreactive fibers. In the dorsolateral subdivision thick dopamine-immunoreactive varicose fibers were found sparsely among diffuse puncta. The ventral subdivision exhibited similar profiles to those in the dorsolateral one, and there were also many characteristic spiral dopamine-immunoreactive fibers of passage. The present study indicates that the dopaminergic structures of the monkey nucleus accumbens differ according to the subterritories, and are morphologically different from those in the caudate-putamen. Q 1997 Elsevier Science Inc.
three subterritories have been demonstrated to have different afferent and efferent projections in the rat (for review, see [10]). Our recent study has demonstrated that the monkey NAC is more complicated than as has been considered, and the caudal part can be subdivided into three subterritories, i.e., medial, dorsolateral, and ventral subdivisions . The dorsolateral subdivision apparently corresponds to the rat core, and both the medial and ventral subdivisions appear to correspond to the rat shell, based on SP and CBD immunoreactivities. The medial subdivision is rich in DA- and neuropeptide (SP and neurotensin) immunoreactive (IR) fibers, whereas the ventral subdivision shows lower densities of DA- and neuropeptide (SP, neurotensin, and enkephalin) IR fibers [13]. It has been demonstrated that DA modulates the synaptic responses distinctly between subdivisions of the NAC [26], and DA depletion or blockage affect the accumbal subdivisions differentially in the rat [3,23,24]. In the monkey NAC, the distribution of D2 blocker-sensitive neurons differed between the subdivisions [13]. Such a functional heterogeneity of DA should be based on the heterogeneity of DA innervation in the NAC. The previous study using DA antibody revealed that monkey NAC medial subdivision possesses extremely dense DA fibers. In addition, unlike the dorsal striatum, the primate NAC receives considerable amounts of noradrenergic fibers [6,30] compared with rodents [27]. Indeed, the study using a noradrenaline antibody revealed many noradrenaline-IR fibers in the dorsomedial region of the monkey NAC [15]. Therefore, it is essential to use the DA antibody, but not the antibody against tyrosine hydroxylase, the synthesizing enzyme of DA, as well as noradrenaline to study the morphological characteristics of DA structures in the NAC of higher mammalian species. The present study was conducted to clarify detailed morphological characteristics of DA-containing structures in the caudal three subterritories of the monkey NAC by employing a DAmonoclonal antibody [7].
KEY WORDS: Immunocytochemistry, Dopamine, Medial subdivision, Dorsolateral subdivision, Ventral subdivision.
INTRODUCTION The nucleus accumbens (NAC) is heavily innervated by midbrain dopaminergic neurons, and is thought to regulate motivated state of behavior. The NAC has been proposed to be involved in the pathogenesis of schizophrenia [1,18] and in the therapeutic action of antipsychotic drugs [23,28]. In the schizophrenic brain, a higher dopamine (DA) content and an increase of dopamine D2 receptors have been reported [1,17–19]. Recent studies have described that the primate NAC is a distinct anatomical territory within the ventral striatum [13,21,22, 25]. The compartmental organization of the NAC is different from that of the striatum, which can be divided into patch and matrix regions [8,38]. According to the recent reviews, the rat NAC can be divided into three subterritories, i.e., shell, core, and rostral pole [38,39]. The core exhibits moderate substance-P (SP) and high calbindin D28 (CBD) immunoreactivities, while the shell shows high SP and moderate CBD immunoreactivities [34,37]. In the core medium-sized cells are packed [36]. These 1
MATERIALS AND METHODS Animals Five adult Japanese monkeys, Macaca fuscata, of both sexes weighing 6–9 kg, were used. The animals were housed and fed for several months in the Institute for Experimental Animals, in Shiga University of Medical Science.
Present address: Department of Anatomy, Fujita Health University, School of Medicine, Toyoake, Aichi, 470-11, Japan.
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Immunocytochemistry Each monkey was deeply anesthetized with ketamine hydrochloride (Ketalar, Sankyo, 25 mg/kg, IM) and sodium pentobarbital (Nembutal, Dainippon Pharm., 10 mg/kg, IV), and perfused through the ascending and descending aorta with 1 liter of 1% sodium pyrosulfite (MBS) in 0.01 M phosphate buffer saline (pH 7.4), followed by the fixative described by Van Eden et al. [32] containing 5% glutaraldehyde (GA) and 1% MBS (pH 7.5). After perfusion for 30 min, the brain was removed from the cranium and cut into 4 mm-thick blocks, followed by postfixation in the solution containing 2% GA and 1% MBS for 3 h. The blocks were then stored in a 0.1 M phosphate buffer (PB) solution containing 15% sucrose, 1% MBS, and 0.1% sodium azide at 47C (pH 7.4). More than 3 weeks later, 30 or 50 mmthick coronal sections were cut using a cryostat [13,14,20]. These sections were stored in the same PB–sucrose–MBS solution. The sections were rinsed in 0.3% Triton X-100 in phosphate buffer saline (0.1 M PBS, pH 7.4, 0.9% NaCl ) for at least 3 days before processing for DA immunohistochemistry. The brain sections were incubated in a primary antibody against DA [7] (dilution of 1:10, 000) for 1 week at 47C, then treated by biotinylated goat antimouse IgG (Vector, diluted 1:1,000 ), followed by the ABC method [12], and finally reacted with 3,3 *diaminobenzidine–hydrogen peroxide solution containing 1% nickel ammonium sulfate [31]. After immunostaining, the sections were mounted onto gelatin-coated glass slides and some were counterstained with neutral red or cresylecht violet. The specificity of immunoreactivity was examined by absorption test. No immunoreactivity was observed. RESULTS Dopamine-IR fibers were observed throughout the NAC. In general, the pattern of distribution of DA-IR fibers was more heterogenous than that in the caudate nucleus and putamen ( Fig. 1 ) . The Medial Subdivision Dopamine-IR fibers were extremely dense in the medial subdivision of the NAC. In most animals, the quantity of DA-IR fibers was the highest in the medial subdivision. In some cases, the marginal area between the dorsolateral and ventral subdivisions showed as many fibers as the medial subdivision (Fig. 1). The delineation between the medial subdivision and the caudate nucleus was readily descernible by not only the EP-line, a linear structure extending from the ventral aspect of the lateral ventricle toward the dorsolateral part of the nucleus [13] (Figs. 1 and 3A and B, thick arrows), but also DA immunoreactivity. Because the medial subdivision contained more DA-IR fibers than the caudate nucleus (Figs. 1, 2B, and 3A). In high-power magnification, a characteristic dense accumulation of DA varicose fibers were observed in this subdivision (Fig. 2A). These fibers were different in shape from those in the dorsolateral subdivision and caudate nucleus (Figs. 2A, C, and D, and 4A–C). As shown in Fig. 3C and D, the medial subdivision was composed of heterogenous compartments with respect to DA content and cytoarchitecture. Although the pattern of distribution of dopaminergic fibers varied according to the compartments within the medial subdivision, quantity of DA fibers did not correlate with the degree of cell concentration. Some areas with densely packed cells in Nissl-stained sections corresponded to DA-poor areas (Fig. 3C and D arrows), while another area with concentrated cells corresponded to a DA-rich area (area ‘‘a’’ of Fig. 3C
FIG. 1. Dopamine (DA)-immunostained section of the caudal nucleus accumbens of the macaque monkey. In the nucleus accumbens (NAC), the distribution of DA-immunoreactive (IR) fibers is more heterogenous compared with that in the caudate nucleus (cn). In the dorsal NAC, the delineation between the caudate nucleus is clear by DA immunoreactivity. The ventromedial margin of the NAC is obscure in the DA immunostained sections. The medial subdivision (M) is most heavily innervated by DA-IR fibers. A part of the dorsolateral subdivision (DL) contains low to moderate quantity of DA-IR fibers. The marginal area of the three subdivision is also intensely DA-IR. Dopamine immunoreactivity of the ventral subdivision (V) is partly low to moderate. Arrow indicates EP-line [13]. The sections are 50-mm thick. Bar Å 1 mm. ic, internal capsule; mC, major island of Calleja; OT, olfactory tubercle; S, septum; ve, lateral ventricle; VP, ventral pallidum.
and D). There were also areas with sparse cells that contained a few DA-IR fibers (area ‘‘b’’ of Fig. 3C and D). Some of the animals showed DA-IR thick varicose fibers and diffuse puncta in the dense DA-IR field, which were similar to those in the dorsolateral subdivision. The distribution pattern differed between the animals. The Dorsolateral Subdivision Low to moderate amount of DA-IR thick varicose fibers were sparsely observed among diffuse DA-IR puncta in the dorsolateral subdivision (Fig. 2B). The varicose fibers were generally more thick than those in the caudate nucleus (Figs. 2B and C and 4B and C). A part of the dorsolateral subdivision showed a dense DA-IR fiber plexus that was similar to those in the medial subdivision (Fig. 2C, arrows), a part of which invaded into the ventral subdivision (Fig. 1).
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FIG. 2. Dopamine-containing fibers in the macaque NAC. The sections are 30-mm thick. Bars Å 100 mm. ( A ) Characteristic dense accumulation of DA-IR varicose fibers in the medial subdivision. ( B ) The dorsal border of the dorsolateral subdivision ( DL ) with the caudate nucleus ( cn ) and the medial border with the medial subdivision ( M ) ( arrows ) . The dorsolateral subdivision ( DL ) possesses less varicose fibers than the medial subdivision ( M ) . ( C ) Thick DA-IR varicose fibers in the dorsolateral subdivision. DA-IR fibers are scattered within diffuse puncta. A part of the dorsolateral subdivision shows a dense DA-IR fiber plexus as observed in the medial subdivision ( arrows ) . ( D ) The caudate nucleus contains fine DA-IR varicose fibers and a few thick DA-IR fibers among the moderately stained numerous diffuse puncta, which are different from the DAIR structures of any subdivision of the NAC.
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FIG. 3. (A,B) Two adjacent sections through dorsal NAC. Dopamine-immunostained section (A) and Nissl-stained section (B). The sections are 30-mm- thick. EP-line [13] is the linear structure that consists of darkly Nissl-stained cells extending from the ventral aspect of the lateral ventricle (ve) into the center of the dorsolateral subdivision (DL). It serves as an anatomical landmark to distinguish the medial subdivision (M) from the caudate nucleus (cn). Note the compactly arranged medium-sized cells in the dorsolateral subdivision (DL) (area surrounded by arrows), which correspond to the rat core. The DA immunoreactivity is the highest in the medial subdivision (M), and less in the dorsal area of the dorsolateral subdivision (DL). Bars Å 1 mm. (C,D) Two adjacent sections throughout the medial subdivision in which the heterogeneity of DA immunoreactivity is conspicuous. The sections are 50-mm thick. White broken lines served as to delineate the DA-rich and DA-poor areas (C). Corresponding areas were delineated by black broken lines on the photomicrograph of the adjacent sections stained with cresylecht violet (D). Areas with densely packed cells in Nissl-stained sections correspond to DA-poor islands (arrows), while another area with concentrated cells correspond to DA-rich area (area ‘‘a’’). There are also areas with sparse cells that contain a few DA-IR fibers (area ‘‘b’’). Dopamine intensity does not correlate with the degree of cell concentrations. Bars Å 200 mm. mC, major island of Calleja.
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FIG. 4. High-power photomicrographs of DA-positive fibers. The sections are 30-mm thick. Bars Å 20 mm. (A) Dense DA-IR fiber plexus in the medial subdivision. (B) Dopamine-IR thick varicose fibers in the dorsolateral subdivision. (C) Dopamine-IR fibers in the caudate nucleus. Many of them are more fine than those in the NAC dorsolateral subdivision.
FIG. 5. Dopamine-containing structures in the ventral subdivision of the macaque NAC. The sections are 30-mm thick. (A) Irregularly arranged DA-IR varicose fibers and characteristic thick spiral fibers of passage (arrows) are observed within diffuse puncta in the ventral subdivision. Bar Å 75 mm. (B) Some of the DA-IR fibers of passage form bundles of five to six fibers within the non-DA-IR fiber bundles (arrows) at the middle and caudal levels of the ventral NAC. Bar Å 100 mm.
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The Ventral Subdivision In the ventral subdivision, the density of DA-IR fibers was mostly low to moderate. But some areas were noted for exceptionally high concentration of DA fibers (Fig. 1), of which distribution varied between individual animals. Irregularly arranged DA-IR varicose fibers were distributed within the ventral subdivision (Fig. 5A and B). The characteristic structures of the ventral subdivision were thick DA-IR fibers of passage that occasionally ran spirally (Fig. 5A, arrows). Some of these DA fibers formed bundles of five to six fibers within the non-DA-IR fiber bundles at middle and caudal levels of the NAC (Fig. 5B, arrows). The boundary between the ventral subdivision and the medial one was obscure in DA immunostained sections (Fig. 1). The dorsolateral border of the NAC with the putamen was also unclear. DISCUSSION This is the first study that detailed the heterogeneity in forms and densities of DA-IR fibers in the three subdivisions of the caudal NAC, i.e., medial, dorsolateral, and ventral subdivisions. The characteristics of DA-IR structures in each NAC subdivision differed markedly, and the patterns of DA fiber distribution were not homogenous even within themselves. Such a heterogeneity in the NAC was more conspicuous in the caudal area than in the rostral area. This finding is in accordance with previous reports in the rat [9,33,34,38]. The present study demonstrated that the medial subdivision possesses a unique DA-positive fiber plexus, which is morphologically distinct from the other two caudal subdivisions and caudate nucleus. An ultrastructural study using the same DA antibody demonstrated that DA-IR terminals in the medial subdivision are large sized (0.33 { 0.27 mm) [14] in comparison with those reported in the monkey striatum using an antibody against tyrosine hydroxylase [29]. In the synaptology, there are more asymmetric junctions of the DA-IR terminals in the medial subdivision than the striatum [14,29]. It was supposed that wiring DA transmission, but not the volume DA transmission [5] predominates in the medial subdivision than in the striatum [14]. The present results provided another evidence showing clear morphological differences between the caudate nucleus and the NAC medial subdivision in the monkey. Our previous study has shown that c- fos expression induced by the DA-blocker haloperidol is enhanced in the NAC, especially in the medial subdivision. This subdivision is rich in neuropeptides and noradrenaline as well as DA [13,15]. Martin et al. [22] demonstrated that glutamate receptors, GluR1 are abundant in the medial subdivision, and ultrastructurally, GluR1-IR dendritic shaft and dendritic spine form asymmetric synapses. At present, precise interaction between DA and glutamate in this area is not clear. In the rat neocortex, DA is thought to inhibit the actions of glutamate in synaptic complex [16]. Among the monkey NAC three subdivisions [13,15], the medial subdivision is likely to correlate most deeply with actions of antipsychotics. This subdivision is recognized to be a putative homologous area of the rat dorsal shell. Interestingly, the rat dorsal shell has not only dense fiber connections between the limbic brain [9,10,35], but also many corticotropin-releasing factor receptors [2]. In addition, the rat shell is also shown to be an acting site of various antipsychotics (for review, see [4]). The previous studies using this DA antibody have shown that ‘‘cone-shaped area’’ in the rat medial NAC is heavily innervated by DA-IR fibers [33,34]. The ‘‘cone-shaped area’’ is reported to be capped by the DA-poor area in the rat NAC [33]. In the
medial subdivision of the monkey NAC, we could not find such DA-poor area dorsal to the DA-rich area. It is clearly a species difference. The correlation between the cell concentration and the DA innervation in rat NAC have been discussed previously [11,33]. For example, Herkenham et al. [11] reported that DA fluorescence is weak in the cell cluster, supporting the idea that the projections from dopaminergic cells in the ventral tegmental area avoid cell clusters. On the other hand, the report of Voorn et al. [33] described that the areas with high DA immunoreactivity avoid areas with dense cell populations on one hand and coincide with the cell-dense area in another. In agreement with Voorn et al., the present study showed that the correlation between the quantity of the DA-IR fibers and the degree of cell concentration was inconsistent in the medial subdivision (Fig. 3C and D). In this study, the dorsolateral subdivision was shown to have somewhat the characteristics of the striatum in DA morphology compared with the other subdivisions. But, the thickness of DAIR fibers was generally more large in the dorsolateral subdivision than in the caudate nucleus. The functions of monkey NAC dorsolateral subdivision are not yet clear. The ventral subdivision exhibited mostly similar profile to DA-containing structures of dorsolateral subdivision. However, in the present study, the characteristic DA-containing structures were demonstrated to be thick spiral fibers of passage in the ventral subdivision. Electron-microscopical studies would clarify further morphological characteristics. At present, being different from the rodent NAC, studies of functional heterogeneity in the primate NAC are very few. In this study, functional aspects of the monkey NAC medial subdivision were discussed. Further studies should be conducted to elucidate the role in the etiology of psychosis and therapeutic actions of this unique cell group in the ventral striatum. ACKNOWLEDGEMENTS
The author thanks to Dr. Geffard (Laboratoire d’Immunologie, Universite´ de Bordeaux II) for providing the antibody against dopamine, Dr. Maeda (Department of Anatomy, Shiga University of Medical Science), Dr. Satoh (Department of Psychiatry, Shiga University of Medical Science), and Dr. Kitahama (De´partement de Me´decine Expe´rimentale, Universite´ Claude Bernard) for their helpful suggestions. This study was supported by Grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture in Japan (B-02454292, C-06670959).
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