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. Author manuscript; available in PMC: 2009 Sep 11.
Published in final edited form as: Adv Behav Biol. 2009 Aug 21;58:239–253. doi: 10.1007/978-1-4419-0340-2_19

Comparative Ultrastructural Analysis of D1 and D5 Dopamine Receptor Distribution in the Substantia Nigra and Globus Pallidus of Monkeys

Michele A Kliem 1, Jean-Francois Pare 1, Zafar U Khan 2, Thomas Wichmann 1,3, Yoland Smith 1,3
PMCID: PMC2742379  NIHMSID: NIHMS90837  PMID: 19750130

Abstract

Dopamine acts through the D1-like (D1, D5) and D2-like (D2, D3, D4) receptor families. Various studies have shown a preponderance of presynaptic dopamine D1 receptors on axons and terminals in the internal globus pallidus (GPi) and substantia nigra reticulata (SNr), but little is known about D5 receptors distribution in these brain regions. In order to further characterize the potential targets whereby dopamine could mediate its effects in basal ganglia output nuclei, we undertook a comparative electron microscopic analysis of D1 and D5 receptors immunoreactivity in the GPi and SNr of rhesus monkeys. At the light microscopic level, D1 receptor labeling was confined to small punctate elements, while D5 receptor immunoreactivity was predominantly expressed in cellular and dendritic processes throughout the SNr and GPi. At the electron microscopic level, 90% of D1 receptor labeling was found in unmyelinated axons or putative GABAergic terminals in both basal ganglia output nuclei. In contrast, D5 receptor labeling showed a different pattern of distribution. Although the majority (65−75%) of D5 receptor immunoreactivity was also found in unmyelinated axons and terminals in GPi and SNr, significant D5 receptor immunolabeling was also located in dendritic and glial processes. Immunogold studies showed that about 50% of D1 receptor immunoreactivity in axons was bound to the plasma membrane providing functional sites for D1 receptor-mediated effects on transmitter release in GPi and SNr. These findings provide evidence for the existence of extrastriatal pre- and post-synaptic targets through which dopamine and drugs acting at D1-like receptors may regulate basal ganglia outflow and possibly exert some of their anti-parkinsonian effects.

1 Introduction

Dopamine is an important modulator of neuronal activity in the basal ganglia circuitry. The most prominent dopaminergic projection originates in the substantia nigra pars compacta (SNc), and terminates in the striatum (Bernheimer et al. 1973, Hornykiewicz and Kish 1987). Degeneration of this pathway is known to contribute to the development of parkinsonism. However, dopamine also reaches basal ganglia areas outside of striatum, including the internal pallidal segment (GPi, Smith et al. 1989, Pifl et al. 1990, Schneider and Rothblat 1991, Whone et al. 2003) and the substantia nigra pars reticulata (SNr, Bernheimer et al. 1973, Geffen et al. 1976, Cheramy et al. 1981). It is, therefore, possible that dopamine loss at these sites may also contribute to the development of parkinsonism. In GPi, dopamine is released from terminals of direct axonal projections from the SNc which, in monkeys, are in large part separate from the nigrostriatal projection (Smith et al. 1989, Jan et al. 2000). By contrast, the dopamine supply to the SNr is through release from dendrites of SNc neurons (Bjorklund and Lindvall 1975, Nieoullon et al. 1978, Arsenault et al. 1988).

The physiological actions of dopamine are mediated through two families of metabotropic receptors, D1-like receptors (D1LRs, Clark and White 1987, Neve 1997) and D2-like receptors (Neve 1997). D1LRs are strongly expressed in the monkey GPi and SNr (Richfield et al. 1987, Besson et al. 1988). D1 receptors are predominately presynaptic in axons and axon terminals of striatopallidal and striatonigral projection neurons (Barone et al. 1987, Fremeau et al. 1991, Mengod et al. 1991, Levey et al. 1993, Yung et al. 1995), where they regulate GABA release (Kliem et al. 2007). The exact location and function of D5 receptors has not been extensively studied, but qualitative immunohistochemical observations revealed that these receptors are expressed at pre- and post-synaptic sites in the rat SNr (Khan et al. 2000). Electrophysiologic studies have shown D5 receptor mediated modulation of neuronal activity in other basal ganglia nuclei (Yan and Surmeier 1997, Baufreton et al. 2003).

In a recent electrophysiologic study in monkeys, we demonstrated that local microinfusions of a D1LR antagonist increased neuronal discharge rates in GPi, suggesting that these receptors are tonically occupied by endogenous dopamine (Kliem et al. 2007). In contrast, infusions of a D1LR agonist significantly reduced the neuronal firing rate in both GPi and SNr. Similar agonist injections in parkinsonian animals resulted in the same effects, demonstrating that D1LRs are functionally active in the dopamine-depleted state (unpublished data). In order to find out whether loss of nigral dopamine neurons influences the location of D1LRs in basal ganglia output nuclei, we compared the cellular and ultrastructural location of D1 and D5 receptor immunoreactivity in the GPi and SNr of normal and parkinsonian monkeys.

2 Materials and Methods

2.1 Animals

Brain tissue from thirteen (D1, n=11; D5, n=7) Rhesus monkeys (Macacca mulatta, 3−10 kg) was used for this study. All experiments were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and the PHS Policy on Humane Care and Use of Laboratory Animals (amended 2002), and were approved by the Institutional Animal Care and Use Committee at Emory University.

2.2 MPTP Administration and Behavioral Assessment

Five of the animals received the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Sigma) i.m. (0.25 mg/kg) twice weekly until a stable parkinsonism was reached. Two of these animals had previously received two MPTP injections into the right carotid artery (0.5 − 0.7 mg/kg per injection). A parkinsonian rating scale, changes in spontaneous cage behavior and automated activity counting procedures (using an infrared beam system) were used to document the degree of MPTP-induced motor disability and its stability. All MPTP-treated animals showed stable parkinsonian motor signs, including bradykinesia, rigidity and postural instability.

2.3 Tissue Preparation

The animals were killed with an overdose of pentobarbital, followed by transcardiac perfusion with paraformaldehyde (4%) and glutaraldehyde (0.1%). The brains were then removed from the skull and cut in 10 mm-thick blocks containing GPi or SNr. Tissue processed for immunocytochemistry was cut in 60 μm sections with a vibratome, rinsed in phosphate-buffered saline (PBS; 0.01 M, pH 7.4), incubated with 1% sodium borohydride solution in PBS, rinsed in PBS, exposed to cyroprotectant, frozen at −80° C, thawed and rinsed in PBS.

2.4 Primary Antisera

The specific monoclonal D1 receptor antibodies used in this study (1:75, Sigma-Aldrich, St. Louis, MO, Levey et al. 1993) were raised in rats against 97 amino acids in the carboxy terminus of the D1 receptor, while the selective D5 receptor antibodies used in this study (1:500, Khan et al. 2000) recognize ten different amino acids in the carboxy terminus of the D5 receptor.

2.5 Immunoperoxidase Procedure

The sections were first exposed for 1 hour at 4° C to a solution containing normal goat serum (10%) and bovine serum albumin (1%) to block non-specific binding. They were then incubated for 48 hours in primary antibody solutions (rat anti-D1 antibodies or rabbit anti-D5 antibodies). Following this, they were incubated in a solution containing biotinylated secondary antibodies (goat anti-rat (D1) antibodies or anti-rabbit (D5) antibodies, Vector Labs, Burlingame, CA; 1:200) followed by the avidin-biotin complex solution (Vectastain Standard Kit, Vector Labs; 1:100). Following rinses in PBS and Tris buffer (0.5 M, pH 7.6) they were exposed to a 10-min incubation in a solution containing imidazole (0.01M; Fisher Scientific, Hampton, NH), hydrogen peroxide (0.006%) and 3−3’-diaminobenzidine tetrahydrochloride (0.025%; Sigma-Aldrich).

After rinses in PBS and phosphate-buffer (PB; 0.1 M, pH 7.4), the sections were post-fixed in osmium tetroxide (1%), followed by washes in PB. Then, a series of incubations in increasing concentrations of alcohol followed by propylene oxide were performed to dehydrate the tissue. Sections were exposed to uranyl acetate (1%) in a 70% alcohol solution to enhance the contrast under the microscope. Finally, the sections were embedded in epoxy resin (Durcupan, ACM; Fluka, Ft. Washington, PA), mounted on microscope slides and placed in the oven (60° C) for two days.

Blocks of GPi and SNr tissue were cut from the microscope slides and glued onto resin blocks. Ultrathin sections (60 nm) were cut with an ultramicrotome (Leica Ultracut T2, Nussloch, Germany) and mounted onto Pioloform-coated single copper grids, and stained with lead citrate.

2.6 Immunogold Procedure

After they were treated with a solution containing milk (5%) and bovine serum albumin (BSA, 1%) in PBS for 1 hour, followed by rinses in Tris-buffered saline-gelatin, sections were transferred to wells containing milk (1%), BSA (1%) and the D1 receptor primary antibody (see above). Next, the sections were rinsed and exposed to goat anti-rat IgGs (1:100) conjugated to 1.4 nm gold particles. Afterwards, they were transferred to the HQ kit (Nanoprobes) for silver intensification of the gold particles (5−10 minutes). The sections were then rinsed with aqueous sodium acetate buffer (2%) and PB, and then treated with osmium tetroxide (0.5% in PB, 0.1 M, pH 7.4). The remainder of the tissue preparation steps was similar to those described for the immunoperoxidase reaction.

2.7 Ultrastructural Analysis

Randomly encountered labeled elements in the immunoperoxidase- or immunogold-processed tissue were photographed under the electron microscope (Zeiss EM 10C, Thornwood, NY) at 16,000 − 25,000X, using an electronic camera (DualView 300W; Gatan, Pleasanton, CA) which was controlled by Digital Micrograph Software (Gatan, Inc., Warrendale, PA; v. 3.6.5). The micrographs were adjusted for brightness and contrast, if needed, with Digital Micrograph or Photoshop software (Adobe Systems, San Jose, CA) to improve the quality of the images for analysis.

For the analysis of immunoperoxidase data, immunoreactive elements from a series of 30−50 electron micrographs were categorized as axons, terminals, dendrites or glial processes. The relative proportion of these elements was calculated and expressed as a percent of total labeled elements in the tissue areas that were examined. The mean percentages and standard deviations (SD) of labeled elements in GPi and SNr of normal and MPTP-treated monkeys were calculated.

For the analysis of immunogold data, silver-intensified gold particles were categorized as plasma membrane-bound or intracellular depending on whether they were in contact with the plasma membrane.

3 Results

3.1 Ultrastructural Localization of D1 Receptor Immunoreactivity in GPi and SNr

At the light microscopic level, the whole extent of the neuropil in GPi and SNr was enriched in D1-receptor-immunoreactive aggregates of small punctate structures, while cell bodies were devoid of immunoreactivity. At the electron microscopic level, the D1 receptor immunoreactivity was mostly located in unmyelinated, pre-terminal axons, accounting for 90.4 ± 2.2% and 89 ± 5.2% of all labeled elements in GPi and SNr, respectively, in normal monkeys (Figs. 1 and 3). The pattern was the same in MPTP-treated parkinsonian monkeys in which the relative proportion of labeled axonal processes was 90.2 ± 0.4% and 88.8 ± 5.9% of total labeled elements in GPi and SNr, respectively.

Figure 1.

Figure 1

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Localization of D1 receptors in GPi and SNr of normal and MPTP-treated monkeys. D1 receptor-immunolabeled unmyelinated axons (Ax) are shown in the GPi and SNr of normal and MPTP-treated monkeys (A-C). An immunoreactive myelinated axon (M.Ax) is also depicted in GPi (A). . D1 receptor immunogold labeling is apposed to the plasma membrane (arrows in D-F) or intracellular (arrowheads in D-F) in unmyelinated axons that travel through GPi and SNr of normal and MPTP-treated monkeys (D-F). Scale bars: 0.5 μm.

Figure 3.

Figure 3

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Comparative distribution of D1 (A) and D5 (B) receptors in axons, dendrites, terminals and glia (B only) in GPi and SNr of normal and MPTP-treated monkeys. D1 receptors were almost exclusively found in unmyelinated axonal segments in the SNr (n=4; surface area (SA), 2936.4 μm2 in normal; n=3; SA, 2202.3 μm2 in MPTP-treated monkeys). A similar pattern of labeling was found in GPi (n=3 in normal; n=3 in MPTP-treated monkeys; SA, 2202.3 μm2). The majority of D5 receptor immunoreactivity was confined to unmyelinated axons in GPi (n=3 in normal; n=3 in MPTP-treated monkeys; SA, 3670.5 μm2) and SNr (n=3 in normal; n=3 in MPTP-treated monkeys; SA, 3450.3 and 3670.5 μm2, respectively). Data are expressed as percentages of immunolabeled elements. Each bar represents the mean ± SD.

In immunogold-labeled tissue from three normal monkeys (Fig. 1), 47.7 ± 1.2% of total gold particles in GPi and 47.8 ± 2.1% of gold labeling in SNr was bound to the axonal plasma membrane. A significant proportion of gold particles were also bound to axonal plasma membranes in GPi (62.1%) and SNr (60.1%) of a parkinsonian monkey.

3.2 Ultrastructural Localization of D5 receptors Immunoreactivity in GPi and SNr

Overall, the pattern of D5 receptor labeling in GPi and SNr resembled that described for D1 receptors (Figs. 2 and 3). We found that 72.0 ± 8.5% of D5 receptor labeling in GPi and 67.0 ± 3.7% of labeling in SNr was expressed in unmyelinated axons. In MPTP-treated monkeys, 74.3 ± 17.6% and 74.8 ± 5.8% of D5 receptor immunoreactivity was found in unmyelinated axons in GPi and SNr, respectively. However, significant D5 receptor immunoreactivity was also detected in dendrites, accounting for 11.0 ± 3.6% of labeling in GPi and 12.0 ± 7.0% in SNr in normal monkeys. In parkinsonian monkeys, 13.5 ± 3.6% of all D5 receptor immunoreactive elements in GPi were in dendrites, while dendritic labeling accounted for 9.7 ± 6.9% of the labeled structures in the SNr.

Figure 2.

Figure 2

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Localization of D5 receptor immunoreactivity in GPi and SNr in normal and MPTP-treated monkeys. (A-D) illustrate D5 receptor immunolabeling in dendrites (Den), unmyelinated axons (Ax) and terminals (Ter) in GPi (A-B) and SNr (C-D) of normal and MPTP-treated monkeys. Occasional glial labeling is also depicted in the SNr (arrowhead in C). Scale bars: 0.5 μm.

4 Discussion

We found that D1 and D5 receptors are predominately located in pre-terminal axons and axon terminals in the GPi and SNr of normal and MPTP-treated parkinsonian monkeys. Our findings also revealed that D5, but not D1 receptors, were significantly expressed postsynaptically in dendrites of GPi and SNr neurons in normal and parkinsonian monkeys. The prominent presynaptic location of D1LRs, presumably on GABAergic terminals of axons originating in the striatum, provides the endogenous dopamine system a means to influence the activity of the basal ganglia output nuclei through presynaptic regulation of striatofugal GABAergic transmission. Pre- and postsynaptic D1LRs may also provide potential targets for therapeutic agents with D1LR activity in Parkinson's disease.

4.1 Localization of D1/D5 receptors in GPi and SNr

As in previous studies in rats, monkeys and humans (Levey et al. 1991, Gnanalingham et al. 1993, Yung et al. 1995, Caille et al. 1996, Betarbet and Greenamyre 2004), we found that D1 receptors are strongly expressed in unmyelinated axons and putative GABAergic axon terminals in GPi and SNr of normal and MPTP-treated monkeys. In immunogold studies, most gold particles were located on axonal plasma membranes in GPi and SNr of normal and parkinsonian monkeys. Therefore, endogenous dopamine or drugs acting at these sites may act to increase GABA efflux and reduce discharge of basal ganglia output neurons in normal and pathological conditions.

Previous qualitative light microscopy studies using in situ hybridization and immunohistochemical techniques demonstrated D5 receptor immunoreactivity on cell bodies and dendrites of GPi and SNr neurons in monkeys (Bergson et al. 1995, Choi et al. 1995, Ciliax et al. 2000), or axons and dendrites in the rat SNr (Khan et al. 2000). Data from our study are in line with those of Kahn et al. (2000), using the same antibodies; D5 receptor immunoreactivity being expressed either presynaptically, in unmyelinated axons and axon terminals, or postsynaptically in dendrites in both basal ganglia output nuclei of normal and MPTP-treated monkeys.

4.2 Functional Consequences of Dopamine D1/D5 Receptor Activation

It is difficult to distinguish pharmacologically between D1 and D5 receptors, and effects of activation of these receptors in GPi and SNr have not been studied separately. It is known, however, that D1LR activation (i.e., combined activation of D1 and D5 receptors) enhances GABA efflux in the rodent and monkey basal ganglia output nuclei (Floran et al. 1990, Aceves et al. 1995, Timmerman and Westerink 1995, Ferre et al. 1996, Rosales et al. 1997, Trevitt et al. 2002, Kliem et al. 2007). It is, therefore, expected that activation of D1LRs at these sites increases GABA release from terminals of the striato-GPi and striatonigral projections, thereby reducing neuronal firing in SNr and GPi. We, indeed, demonstrated recently that administration of the selective dopaminergic D1LR agonist, SKF82958, significantly reduced neuronal discharge in GPi and SNr of normal monkeys (Kliem et al. 2007), as was previously shown for neurons in the rat SNr and entopeduncular nucleus (Timmerman and Abercrombie 1996, Radnikow and Misgeld 1998, Floran et al. 2002, Windels and Kiyatkin 2006).

Comparatively, little is known about potential changes of D1LR function in the parkinsonian state. Studies using rat brain slices from dopamine-depleted animals have shown that D1LR effects on GABAergic transmission in the entopeduncular nucleus are reduced compared to the normal state (Floran et al. 1990, Aceves et al. 1995). In vivo electrophysiologic studies showed that systemically administered D1LR agonists reduce firing rates of SNr neurons in dopamine-depleted rats (Waszczak et al. 1984, Weick and Walters 1987). We have also recently demonstrated that local activation of D1LRs significantly inhibits GPi and SNr cells in MPTP-treated monkeys (Kliem et al., unpublished data), suggesting that D1LR-mediated effects are retained after dopamine depletion, consistent with the ultrastructural data presented in this study. Despite significant dopamine depletion and clear behavioral signs of parkinsonism, no significant change was found in the location or function of D1LRs in GPi and SNr of MPTP-treated monkeys (Kliem et al., unpublished data). At first glance, these observations appear to be in contrast with findings from the striatum showing that dopamine depletion induces significant changes in binding, affinity, and, presumably, function of D1LR in striatal projection neurons (Gagnon et al. 1990, Graham et al. 1993, Blanchet et al. 1996, Betarbet and Greenamyre 2004). However, it is noteworthy that our study did not attempt at characterizing the pharmacological properties of D1LRs, nor provide any direct evidence for absolute decrease or increase in the total number of D1 or D5 receptor immunoreactive elements in basal ganglia output nuclei of parkinsonian monkeys.

4.3 Dopamine D1/D5 Receptor Activation May Influence Behavior

Studies in the rat have demonstrated that D1LR blockade in the SNr impairs motor activity and increases EMG activity and rigidity (Hemsley and Crocker 2001, Trevitt et al. 2001, Bergquist et al. 2003), suggesting that dendritic dopamine release in the nigra plays a role in regulating basal ganglia-related motor behaviors. Thus far, there is no clear evidence for a functionally significant dopaminergic tone in the monkey SNr, although our previous experiments have demonstrated that D1LR may be tonically activated by ambient dopamine in GPi. Degeneration of the SNc-GPi projection may also contribute to the development of some of the abnormal behaviors associated with parkinsonism because lower dopamine concentrations have been reported in GPi of parkinsonian patients (Bernheimer et al. 1973) and MPTP-treated monkeys (Pifl et al. 1992). Systemic administration of drugs with D1LR activity improves motor symptoms of parkinsonism in MPTP-treated monkeys (Blanchet et al. 1996, Goulet and Madras 2000). Based on findings presented in this and our functional studies (Kliem et al., unpublished, and Kliem et al. 2007), it is reasonable to believe that some of these behavioral effects may be mediated through modulation of GPi neuronal activity. Due to the limited knowledge about the localization and function of D5 receptors and the overall greater number of D1 receptors in the brain, most physiological and behavioral effects of mixed D1/D5-receptor agonist in the brain have been attributed to activation of D1 receptors. However, because dopamine has a higher affinity for the D5 receptor subtype, combined with our findings showing that D5 receptors are located to subserve pre- and post-synaptic regulation of neuronal activity in basal ganglia output nuclei, we should consider that D5 receptors may have a more significant role in normal and pathological basal ganglia functions than previously thought (Grandy et al. 1991, Sunahara et al. 1991, Tiberi et al. 1991).

Recently it has become possible to study the functions of D1 and D5 receptors separately, by genetic inactivation of one of the two receptor subtypes. These studies suggested that D1 receptor stimulation may facilitate movement, while D5 receptor stimulation may have an opposite effect on motor activity. For instance, intracerebroventricular administration of an antisense oligodeoxynucleotide against the D5 receptor in dopamine-depleted rats blocks D1LR agonist-induced contralateral turning (Dziewczapolski et al. 1998). This is further supported by the observation that D5 receptor knock-out mice are hyperactive (Sibley 1999), whereas D1 receptor knockout mice show reduced motor activity (Centonze et al. 2003). Hopefully, the future development of selective D1 or D5 receptor agonists and antagonists will open up the possibility to clearly assess the functional roles of each of these receptors individually in normal monkeys or in animal models of parkinsonism.

4.4 Functional Significance of D1LRs-Mediated Effects in Parkinsonism

Our study demonstrates that the overall pattern of D1LR expression in both basal ganglia output nuclei is unchanged after dopamine depletion in MPTP-treated monkeys, suggesting that D1LR-mediated effects may not be significantly affected in Parkinson's disease, and therefore, remain potential therapeutic targets. Dopamine replacement therapies aimed at the SN, indeed, support this view. For instance, glia-derived neurotrophic factor infusions (Gerhardt et al. 1999) and fetal mesencephalic tissue grafts (Starr et al. 1999) in the SN ameliorate parkinsonian motor signs in adult MPTP-treated monkeys, underlining the importance of dendritic dopamine release in mediating parkinsonism in primates. Our results suggest that enhancing dopamine release in GPi in parkinsonism may also be a useful therapeutic strategy for parkinsonism. Therapies that exploit the prokinetic effects of D1 receptor activation, and possibly D5 receptor antagonism, could also be particularly useful.

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