Midbrain dopaminergic neurons in the mouse: Computer-assisted mapping

The dopaminergic (DA) neurons in the midbrain play a role in cognition, affect and movement. The purpose of the present study was to map and quantify the number of DA neurons in the midbrain, within the nuclei that constitute cell groups A8, A9 and A10, in the mouse. Two strains of mice were used; the C57BL/6 strain was chosen because it is commonly used in neurobiological studies, and the FVB/N strain was chosen because it is used frequently in transgenic studies. DA neurons were identified, in every fifth 20-μm-thick coronal section, using an antibody against tyrosine hydroxylase. Cell locations were entered into a computer imaging system. The FVB/N strain has 42% more midbrain DA neurons than the C57BL/6 strain; on one side of the brain there were 15,135 ± 356 neurons (mean ± S.E.M.) in the FVB/N strain, and 10,645 ± 315 neurons in the C57BL/6 strain. In both strains, approximately 11% of the neurons were located in nucleus A8 (the DA neurons in the retrorubral field), 38% in nucleus A9 (the DA neurons in the substantia nigra pars compacta, pars reticulata, and pars lateralis), and 51% in nucleus A10 (the DA neurons in midline regions such as the ventral tegmental area, central linear nucleus, and interfascicular nucleus). The number of midbrain DA cells, and their distribution within the three nuclear groups, is discussed with respect to findings in other species. © 1996 Wiley-Liss, Inc.     

Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and walking in the rat

Single unit activity of dopamine and non-dopamine neurons in the substantia nigra and ventral tegmental area was recorded across stages of sleep and waking in the rat. These stages consisted of slow wave sleep (SWS), rapid eye movement (REM) sleep, awake-quiet (AQ) and awake-moving (AM). The dopamine neurons showed no change in mean firing rate across the stages of sleep or waking. During REM sleep, however, the dopamine cells fired with a more variable interspike interval than during SWS. In contrast, non-dopamine neurons in the substantia nigra and ventral tegmental area showed large increases in firing rate in REM compared to SWS, and in AM compared to AQ, without showing changes in interspike interval variability. In conclusion, whereas other monoaminergic neurons and various cortical and subcortical neurons exhibit marked changes in firing rate across the stages of sleep and waking, the dopamine neurons are unique in their lack of change in firing rate across stages.     

Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and waking in the rat

Single unit activity of dopamine and non-dopamine neurons in the substantia nigra and ventral tegmental area was recorded across stages of sleep and waking in the rat. These stages consisted of slow wave sleep (SWS), rapid eye movement (REM) sleep, awake-quiet (AQ) and awake-moving (AM). The dopamine neurons showed no change in mean firing rate across the stages of sleep or waking. During REM sleep, however, the dopamine cells fired with a more variable interspike interval than during SWS. In contrast, non-dopamine neurons in the substantia nigra and ventral tegmental area showed large increases in firing rate in REM compared to SWS, and in AM compared to AQ, without showing changes in interspike interval variability. In conclusion, whereas other monoaminergic neurons and various cortical and subcortical neurons exhibit marked changes in firing rate across the stages of sleep and waking, the dopamine neurons are unique in their lack of change in firing rate across stages.     

Contrasting effects of repeated treatment vs. withdrawal of methamphetamine on tyrosine hydroxylase messenger RNA levels in the ventral tegmental area and substantia nigra zona compacta of the rat brain

We have assessed the effect of repeated treatment with methamphetamine (METH) on the abundance of the messenger ribonucleic acid molecules encoding the enzyme tyrosine hydroxylase (TH) and preprocholecystokinin (PPCCK) in the substantia nigra zona compacta (SNc) and the ventral tegmental area (VTA) by in situ hybridization histochemistry. Rats were injected twice daily with METH (4 mg/kg of body weight) for 6 consecutive days and sacrificed either 5 h or 15 days after the last injection. TH mRNA in the VTA was unaffected by repeated METH treatment but was decreased 25% relative to controls in the SNc. Concurrent administration of METH and MK-801 decreased TH mRNA levels in the SNc to 47% relative to controls. In contrast, TH mRNA levels were found increased in the VTA (42%) but not SNc 15 days post-METH treatment. Coadministration of MK-801 with METH prevented the increase in TH mRNA in the VTA. PPCCK mRNA levels were not significantly affected by METH treatment in VTA or SNc either 5 h or 15 days posttreatment. The results demonstrate that exposure to repeated methamphetamine elicits changes of TH mRNA levels in the VTA that become manifest 2 weeks after withdrawal from this psychostimulant drug. © 1996 Wiley-Liss, Inc.     

c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery

Evidence suggests that dopaminergic neurons of the ventral mesencephalic tegmentum (VMT) could be important for paradoxical sleep (PS). Here, we examined whether dopamine (DA) and adjacent gamma-aminobutyric acid (GABA)-synthesizing neurons are active in association with PS recovery as compared to PS deprivation or control conditions in different groups of rats by using c-Fos expression as a reflection of neural activity, combined with dual immunostaining for tyrosine hydroxylase (TH) or glutamic acid decarboxylase (GAD). Numbers of TH+/c-Fos+ neurons in the substantia nigra (SN) were not significantly different across groups, whereas those in the ventral tegmental area (VTA) were significantly different and greatest in PS recovery. Numbers of GAD+/c-Fos+ neurons in both VTA and SN were greatest in PS recovery. Thus, DA neuronal activity does not appear to be suppressed by local GABAergic neuronal activity during PS but might be altered in pattern by this inhibitory as well as other excitatory, particularly cholinergic, inputs such as to allow DA VTA neurons to become maximally active during PS and thereby contribute to the unique physiological and cognitive aspects of that state.     

Asymmetry in functional connectivity of the human habenula revealed by high‐resolution cardiac‐gated resting state imaging

The habenula is a hub for cognitive and emotional signals that are relayed to the aminergic centers in the midbrain and, thus, plays an important role in goal‐oriented behaviors. Although it is well described in rodents and non‐human primates, the habenula functional network remains relatively uncharacterized in humans, partly because of the methodological challenges associated with the functional magnetic resonance imaging of small structures in the brain. Using high‐resolution cardiac‐gated resting state imaging in healthy humans and precisely identifying each participants' habenula, we show that the habenula is functionally coupled with the insula, parahippocampus, thalamus, periaqueductal grey, pons, striatum and substantia nigra/ventral tegmental area complex. Furthermore, by separately examining and comparing the functional maps from the left and right habenula, we provide the first evidence of an asymmetry in the functional connectivity of the habenula in humans. Hum Brain Mapp 37:2602–2615, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc .     

Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs within midbrain dopamine neurons

Many behavioral effects of nicotine result from activation of nigrostriatal and mesolimbic dopaminergic systems. Nicotine regulates dopamine release not only by stimulation of nicotinic acetylcholine receptors (nAChRs) on dopamine cell bodies within the substantia nigra and ventral tegmental area (SN/VTA), but also on presynaptic nAChRs located on striatal terminals. The nAChR subtype(s) present on both cell bodies and terminals is still a matter of controversy. The purpose of this study was to use double-labeling in situ hybridization to identify nAChR subunit mRNAs expressed within dopamine neurons of the SN/VTA, by using a digoxigenin-labeled riboprobe for tyrosine hydroxylase as the dopamine cell marker and (35)S-labeled riboprobes for nAChR subunits. The results reveal a heterogeneous population of nAChR subunit mRNAs within midbrain dopamine neurons. Within the SN, almost all dopamine neurons express alpha2, alpha4, alpha5, alpha6, beta2, and beta3 nAChR mRNAs, with more than half also expressing alpha3 and alpha7 mRNAs. In contrast, less than 10% express beta4 mRNA. Within the VTA, a similar pattern of nAChR subunit mRNA expression is observed except that most subunits are expressed in a slightly lower percentage of dopamine neurons than in the SN. Within the SN, alpha4, beta2, alpha7, and beta4 mRNAs are also expressed in a significant number of nondopaminergic neurons, whereas within the VTA this only occurs for beta4. The heterogeneity in the expression of nAChR subunits within the SN/VTA may indicate the formation of a variety of different nAChR subtypes on cell bodies and terminals of the nigrostriatal and mesolimbic pathways.     

Mesostriatal and mesolimbic projections of midbrain neurons immunoreactive for estrogen receptor beta or androgen receptors in rats

The dopamine (DA) inputs to the caudate putamen, the nucleus accumbens, and the amygdala in rats are sensitive to circulating estrogens and androgens. One mechanism for the hormone modulation of these systems may be via actions at cognate intracellular estrogen and androgen receptors. However, although it is known that specific subsets of midbrain DA neurons are immunopositive for estrogen receptor beta (ERbeta) or androgen receptors (ARs), it is not known where these receptor-bearing cells project. To address this issue, we combined double-label immunocytochemistry with retrograde tract tracing to identify the forebrain projections of ERbeta- or AR-immunoreactive (IR) midbrain neurons. Specifically, Fluoro-Gold and/or cholera toxin were injected into discrete subregions of the caudate-putamen, the nucleus accumbens, or the amygdala. Evaluations of the resultant midbrain labeling revealed that ERbeta-IR neurons sent collateral projections mainly to both the ventral caudate-putamen and the amygdala, but not to the dorsal caudate or nucleus accumbens. In contrast, AR-IR neurons projected either to the amygdala or the nucleus accumbens but not to the caudate-putamen. The organization of these forebrain projections concurs with some of the known hormone sensitivities of mesostriatal and mesolimbic DA systems in rats and provides an anatomical model that predicts separate influences for androgens and estrogens over mesostriatal and mesolimbic DA systems.     

Subpopulations of mesencephalic dopaminergic neurons express different levels of tyrosine hydroxylase messenger RNA.

Subpopulations of mesencephalic dopamine containing neurons possess different electrophysiological, pharmacological, biochemical, and anatomical properties. In order to determine whether such differences are related to the regulation of tyrosine hydroxylase, the rate limiting enzyme in the synthesis of catecholamines, the regional distribution of tyrosine hydroxylase messenger RNA in these neurons was examined using in situ hybridization histochemistry. In the mouse, labelling for tyrosine hydroxylase messenger RNA associated with individual neurons was significantly less in the lateral substantia nigra pars compacta than in the medial substantia nigra pars compacta and the ventral tegmental area. A similar pattern of labelling was observed in the rat. Labelling for tyrosine hydroxylase messenger RNA was significantly less in the lateral substantia nigra pars compacta than in medial pars compacta (a densely cellular region), the area dorsal to the medial substantia nigra pars compacta (a less cell dense region), and the ventral tegmental area. Differences in levels of labelling for messenger RNA in mesencephalic dopamine neurons were not related to differences in cell size as measured in sections processed for tyrosine hydroxylase immunohistochemistry. The results suggest that tyrosine hydroxylase messenger RNA is differentially regulated in subpopulations of mesencephalic dopamine neurons, supporting the view that these neurons are physiologically distinct.     

Mechanisms regulating spill‐over of synaptic glutamate to extrasynaptic NMDA receptors in mouse substantia nigra dopaminergic neurons

N‐Methyl‐d ‐aspartate glutamate receptors (NMDARs) contribute to neural development, plasticity and survival, but they are also linked with neurodegeneration. NMDARs at synapses are activated by coincident glutamate release and depolarization. NMDARs distal to synapses can sometimes be recruited by ‘spill‐over’ of glutamate during high‐frequency synaptic stimulation or when glutamate uptake is compromised, and this influences the shape of NMDAR‐mediated postsynaptic responses. In substantia nigra dopamine neurons, activation of NMDARs beyond the synapse during different frequencies of presynaptic stimulation has not been explored, even though excitatory afferents from the subthalamic nucleus show a range of firing frequencies, and these frequencies change in human and experimental Parkinson's disease. This study reports that high‐frequency stimulation (80 Hz/200 ms) evoked NMDAR‐excitatory postsynaptic currents (EPSCs) that were larger and longer lasting than those evoked by single stimuli at low frequency (0.1 Hz). MK‐801, which irreversibly blocked NMDAR‐EPSCs activated during 0.1‐Hz stimulation, left a proportion of NMDAR‐EPSCs that could be activated by 80‐Hz stimulation and that may represent activity of NMDARs distal to synapses. TBOA, which blocks glutamate transporters, significantly increased NMDAR‐EPSCs in response to 80‐Hz stimulation, particularly when metabotropic glutamate receptors (mGluRs) were also blocked, indicating that recruitment of NMDARs distal to synapses is regulated by glutamate transporters and mGluRs. These regulatory mechanisms may be essential in the substantia nigra for restricting glutamate diffusion from synaptic sites and keeping NMDAR‐EPSCs in dopamine neurons relatively small and fast. Failure of glutamate transporters may contribute to the declining health of dopamine neurons during pathological conditions.     

Electrical stimulation of mesencephalic cell groups (A9-A10) produces monosynaptic excitatory potentials in rat frontal cortex

Electrical stimulation of the ventral tegmental area and substantia nigra produces monosynaptic and polysynaptic excitatory postsynaptic potentials in rat frontal neurons that can be recorded intracellularly. The electrophysiological characteristics of the monosynaptic responses and the possibility that dopamine (DA) mediates these events are discussed.     

Forebrain projections from cholecystokininlike-immunoreactive neurons in the rat midbrain

The purpose of the present study was to analyze the distribution of cholecystokininlike-immunoreactive (CCK-I) neurons within the rat ventral mesencephalon which project to several forebrain areas. The peroxidase-antiperoxidase immunocytochemical technique was used to examine the anatomical localization of CCK-I within the ventral midbrain and in the following forebrain regions: caudate-putamen, nucleus accumbens, olfactory tubercle, bed nucleus of the stria terminalis, septum, amygdala, and prefrontal, anterior cingulate, and piriform cortices. CCK-I perikarya were distributed throughout the substantia nigra, ventral tegmental area, and several midline raphe nuclei to a greater extent than previously reported, particularly in the substantia nigra pars compacta. Terminallike immunoreactivity for CCK was observed in all of the above forebrain sites. In addition, infrequent CCK-I cell bodies were localized in the caudate-putamen, nucleus accumbens, olfactory tubercle, septum, and bed nucleus of the stria terminalis. To analyze forebrain projections of the ventral midbrain CCK-I neurons, indirect immunofluorescence was combined with fluorescence retrograde tracing. CCK-I neurons of the substantia nigra and/or ventral tegmental area were found to project, to varying extents, to all of the above CCK-I forebrain terminal fields. The nucleus accumbens, olfactory tubercle, and septal and prefrontal cortical projections arose primarily from CCK-I perikarya in the ventral tegmental area whereas the projections to the caudate-putamen and anterior cingulate cortex arose predominantly from immunoreactive neurons in the substantia nigra pars compacta. The amygdala received innervation mainly from CCK-I cell bodies located in the substantia nigra pars lateralis. CCK-I afferents to the bed nucleus of the stria terminalis and piriform cortex originated from perikarya distributed approximately equally across the ventral tegmental area and substantia nigra pars compacta. The general topography of CCK-I forebrain innervation observed in this study is similar to that previously reported for the ascending dopaminergic projections from ventral mesencephalic neurons. CCK-I neurons of the midline raphe nuclei were found to provide relatively minor afferents to the caudate-putamen, bed nucleus of the stria terminalis, septum, and prefrontal cortex and more substantial projections to the amygdala. The results of this study demonstrate that CCK-I neurons of the ventral midbrain supply a much broader innervation of forebrain regions than previously appreciated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Altered mesencephalic dopaminergic populations in adulthood as a consequence of brief perinatal glucocorticoid exposure

Early exposure to stressors is strongly associated with enduring effects on central nervous system function, but the mechanisms and neural substrates involved in this biological 'programming' are unclear. This study tested the hypothesis that inappropriate exposure to glucocorticoid stress hormones (GCs) during critical periods of development permanently alters the mesencephalic dopaminergic populations in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Using a rat model, the synthetic GC dexamethasone was added to the maternal drinking water during gestational days 16-19 or over the first week of postnatal life. In adulthood, the effects upon tyrosine hydroxylase immunopositive (TH+) cell numbers in the midbrain, and monoamine levels in the forebrain, of the adult offspring were assessed and compared with control offspring whose dams received normal drinking water. In the VTA, both prenatal and postnatal dexamethasone treatment increased TH+ cell numbers by approximately 50% in males and females. Although prenatal dexamethasone treatment also increased TH+ cell numbers in the SNc by 40-50% in males and females, postnatal treatment affected females only by increasing TH+ cell numbers by approximately 30%. In comparison, similar changes were not detected in the monoamine levels of the dorsolateral striatum, nucleus accumbens or infralimbic cortex of either males or females, which is a feature likely to reflect adaptive changes in these pathways. These studies demonstrate that the survival or phenotypic expression of VTA and SNc dopaminergic neurones is profoundly influenced by brief perinatal exposure to GCs at times when endogenous levels are normally low. These findings are the first to demonstrate permanent changes in the cytoarchitecture within midbrain dopamine nuclei after perinatal exposure to stress hormones and implicate altered functionality. Thus, they have significance for the increasing use of GCs in perinatal medicine and indicate potential mechanisms whereby perinatal distress may predispose to the development of a range of psychiatric conditions in later life.     

The effect of the acute and chronic administration of CP 96,345, a selective neurokinin1 receptor antagonist,on midbrain dopamine neurons in the rat: A single unit,extracellular recording study

In this study, we examined the effect of acute and chronic administration of the selective neurokinin₁ receptor antagonist CP 96,345 on the basal activity of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA). This was accomplished using the technique of in vivo, extracellular single unit recording in anesthetized rats. The intravenous (i.v.) administration of CP 96,345 (0.01–1.28 mg/kg) did not significantly alter the firing rate of spontaneously active DA neurons in the SNC and VTA areas. The acute administration of 5 or 10 mg/kg, i.p., of CP 96,345 produced a significant decrease in the number of spontaneously active SNC and VTA dopamine cells compared to vehicle-treated rats. In contrast to its effect on the number of spontaneously active DA neurons, the administration of 5 mg/kg, i.p., of CP 96,345 did not significantly alter the basal firing pattern of either SNC or VTA DA neurons. The acute administration of CP 96,345 (10 mg/kg, i.p.) significantly potentiated the suppressant action of (+)-apomorphine on the basal firing rate of spontaneously active SNC and VTA DA cells. The chronic administration of CP 96,345 (5 or 10 mg/kg, i.p.) for 21 days also produced a significant decrease in the number of spontaneously active SNC and VTA DA cells compared to vehicle controls. This effect was not reversed by the systemic administration of (+)-apomorphine (50 μg/kg, i.v.), suggesting that the reduction in the number of spontaneously active DA cells produced by CP 96,345 is probably not the result of depolarization inactivation. Overall, our results indicate that the tonic activation of NK₁ receptors by substance P may be necessary to maintain the spontaneous activity of a proportion of midbrain DA neurons. © 1996 Wiley-Liss, Inc.     

Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry

To verify the possibility that the pedunculopontine nucleus is a source of glutamatergic terminals in contact with midbrain dopaminergic neurons in the squirrel monkey, we used the anterograde transport of Phaseolus vulgaris-leucoagglutinin in combination with preembedding immunohistochemistry for tyrosine hydroxylase and for calbindin D-28k and postembedding immunocytochemistry for glutamate and for γ-aminobutyric acid. Following tracer injections in the pedunculopontine nucleus, numerous anterogradely labeled fibers emerged from the injection sites to innervate densely the pars compacta of the substantia nigra and ventral tegmental area. The major type of labeled fibers were thin with multiple collaterals and varicosities that established intimate contacts with midbrain dopaminergic neurons. At the electron microscopic level, the anterogradely labeled boutons were medium sized (maximum diameter between 0.9 μm and 2.5 μm) and contained numerous round vesicles and mitochondria. Postembedding immunocytochemistry revealed that 40–60% of anterogradely labeled terminals were enriched in glutamate and formed asymmetric synapses with dendritic shafts of substantia nigra and ventral tegmental area neurons. In triple-immunostained sections, some of the postsynaptic targets to these terminals were found to be dopaminergic. In addition, 30–40% of the anterogradely labeled terminals in both regions displayed immunoreactivity for γ-aminobutyric acid and, in some cases, formed symmetric synapses with dendritic shafts. In conclusion, our results provide the first ultrastructural evidence for the existence of synaptic contacts between glutamate-enriched terminals from the pedunculopontine nucleus and midbrain dopaminergic neurons in primates. Our results also show that the pedunculopontine nucleus is a potential source of γ-aminobutyric acid input to this region. These findings suggest that the pedunculopontine nucleus may play an important role in the modulation of the activity of midbrain dopaminergic cells by releasing glutamate or γ-aminobutyric acid as neurotransmitter. © 1996 Wiley-Liss, Inc.     

Acetylcholinesterase neurons in dopamine-containing regions of the brain

Summary A pharmaco-histochemical regimen was used to examine the morphology and internal organization of acetylcholinesterase (AChE, EC 3.1.1.7) neurons in brain areas—the caudate-putamen nucleus, nucleus accumbens, olfactory tubercule, and substantia nigra—monoaminergically characterized in terms of their dopamine content. Intense, homogenous staining is produced in these neural regions by other histochemical protocols for AChE; individual AChE-containing neurons cannot be observed reliably or consistently. With the present technique, based on the differential regeneration of AChE in the separate subcellular compartments of the neuron (i.e., axon, dendrite, soma) after intramuscular injection ofbis-(1-methylethyl)-phosphorofluoridate (di-isopropylfluorophosphate: DFP), it was shown that AChE was associated with neurons whose cell bodies lay within the brain areas studied. Although the significance of dopaminergic-cholinergic relationships in the caudate-putamen complex, nucleus accumbens, and olfactory tubercule could not be established on the basis of these new histochemical data, arguments were presented indicating that dopamine neurons in the zona compacta of the substantia nigra also contained AChE.     

A topographic localization of enkephalin on the dopamine neurons of the rat substantia nigra and ventral tegmental area demonstrated by combined histofluorescence-immunocytochemistry

The concentration of choline acetyltransferase, a specific marker for cholinergic neurons, was determined in the supraoptic nucleus after a variety of lesions. Surgical lesions immediately rostral as well as medial and lateral to the nucleus did not affect the concentration of the enzyme. Only lesions which separated the nucleus from the posterior part of the lateral hypothalamus slightly decreased its concentration in choline acetyltransferase. It is concluded that the bulk of the cholinergic neurons is in the supraoptic nucleus or its immediate vicinity.     

Synaptic innervation of midbrain dopaminergic neurons by glutamate-enriched terminals in the squirrel monkey

The excitatory amino acid, glutamate, has long been thought to be a transmitter that plays a major role in the control of the firing pattern of midbrain dopaminergic neurons. The present study was aimed at elucidating the anatomical substrate that underlies the functional interaction between glutamatergic afferents and midbrain dopaminergic neurons in the squirrel monkey. To do this, we combined preembedding immunocytochemistry for tyrosine hydroxylase and calbindin D-28k with postembedding immunostaining for glutamate. On the basis of their ultrastructural features, three types (so-called types I, II, and III) of glutamate-enriched terminals were found to form asymmetric synapses with dendrites and perikarya of midbrain dopaminergic neurons. The type I terminals accounted for more than 70% of the total population of glutamate-enriched boutons in contact with dopaminergic cells in the dorsal and ventral tiers of the substantia nigra pars compacta as well as in the ventral tegmental area, whereas 5–20% of the glutamatergic synapses with dopaminergic neurons involved the two other types of terminals. The major finding of our study is that the glutamate-enriched boutons were involved in 70% of the axodendritic synapses in the ventral tegmental area. In contrast, less than 40% of the boutons in contact with dopaminergic dendrites were immunoreactive for glutamate in the dorsal and ventral tiers of the substantia nigra pars compacta. Approximately 50% of the terminals in contact with the perikarya of the different populations of midbrain dopaminergic neurons displayed glutamate immunoreactivity. In conclusion, our findings provide the first evidence that glutamate-enriched terminals form synapses with midbrain dopaminergic neurons in primates. The fact that the proportion of glutamatergic boutons in contact with dopaminergic cells is higher in the ventral tegmental area than in the substantia nigra pars compacta suggests that the different groups of midbrain dopaminergic neurons are modulated differently by extrinsic glutamatergic afferents in primates. © 1996 Wiley-Liss, Inc.