Substantia Nigra Compacta Research Articles

A model for narcolepsy.

A model for narcolepsy is developed on the basis of data obtained from brains collected at post mortem from three patients with narcolepsy. The concentration of dopamine, noradrenaline, and serotonin and their metabolites was measured in many brain regions. The number and affinity of the 3-H-spiperone and 3-H-prazocin binding sites was also measured in many of these regions to characterize the D-2 dopamine and alpha-1-noradrenergic receptors, respectively. Evidence for significantly increased serotonin levels and serotonin turnover was found in many brain regions. Noradrenaline turnover was increased in the frontal cortex. DOPAC/DA was significantly reduced in the striatum. The number of D-2 dopamine receptors, however, was markedly increased in this region. The number of alpha-1-noradrenergic receptors was significantly decreased in the frontal cortex and amygdala. Our neurochemical data demonstrating increased NA and 5-HT turnover suggest that locus coeruleus noradrenergic neurones and raphe serotonergic neurones are overactive in narcolepsy. Current evidence posits that increased activity in these neurones depresses the activity of cholinergic pedunculopontine (PP) REM sleep effector neurones. PP neurones project to and stimulate the dopaminergic substantia nigra compacta neurones. Decreased PP activity in narcolepsy, thus, could lead to pontine cholinergic supersensitivity and could also reduce the firing rates of dopaminergic neurones, as the low striatal ratio of DOPAC/DA suggests. An increase in the number of D-2 dopamine receptors in the striatum may result. The reason for the increased activity of the noradrenergic and serotonergic neurones remains to be determined, but immune inactivation of alpha-1-noradrenergic receptors may be the initiating event. Low alpha-1-noradrenergic receptor numbers may account for the chronic drowsiness of narcolepsy. The repeated entry into sleep, and into REM sleep in particular, may represent a homeostatic response to increase these receptor numbers and, thus, to increase alertness. Some therapeutic implications of this model are presented in the discussion.

Disappearance of GAD-mRNA and tyrosine hydroxylase in substantia nigra following striatal ibotenic acid lesions: Evidence for transneuronal regression

Transneuronal regression in substantia nigra reticulata (SNR) and substantia nigra compacta (SNC) neurons was studied in Fischer 344 male rats by immunocytochemistry and by in situ hybridization. Three months after striatal lesioning by ibotenic acid, there was a shrinkage (30%) of the SNR region cross-sectional area and a 50% disappearance of neurons that contain glutamic acid decarboxylase (GAD)-mRNA, but only in the ventromedial portion of this nucleus. Loss of dopaminergic neurons, as recognized by tyrosine hydroxylase immunoreactivity, occurred only in caudal portions of the SNC and SNR. These findings suggest that lasions in reciprocally connected pathways, like the nigrostriatal and striatonigral systems, may produce a vicious cycle (feedforward cascade) of neurodegeneration due to interference with retrograde and anterograde influences.

Distribution of GAP-43 mRNA in the brain stem of adult rats as evidenced by in situ hybridization: localization within monoaminergic neurons

Using in situ hybridization, we examined the distribution of the mRNA encoding for the growth-associated protein GAP-43 in the brain stem of adult rats. GAP-43 was expressed at the highest level in the nucleus raphe dorsalis (NDR), nucleus centralis superior (NCS), substantia nigra compacta (SNc), ventral tegmental area (VTA), and locus coeruleus (LC). An intermediate level of signal was detected over the periaque-ductal gray, superior colliculi, and thalamic region, and no significant signal was detected in the substantia nigra pars reticulata and red nucleus. The hybridization signals of GAP-43 mRNA and tryptophan hydroxylase mRNA completely overlapped in the NDR and NCS, and signals for GAP-43 mRNA and tyrosine hydroxylase mRNA overlapped in the SNc, VTA, and LC. The disappearance of the hybridization signal for GAP-43 mRNA after intracerebroventricular injections of the neurotoxins 5,7-dihydroxytryptamine (5,7-DHT) or 6-hydroxydopamine (6-OHDA) indicated that high levels of GAP-43 are synthesized in the serotonergic neurons of the raphe nuclei and in the catecholaminergic neurons of the SNc, VTA, and LC. In light of the role of GAP-43 in axonal outgrowth, modulation of signal transduction, and release of different neurotransmitters in the adult CNS, this phosphoprotein might be involved in the functional plasticity and synaptic transmission of monoaminergic neurons.

Immunocytochemical localization of calretinin in the forebrain of the rat

The distribution of the calcium binding protein calretinin (protein 10) was examined in the rat forebrain by immunohistochemistry. The main and accessory olfactory bulbs had immunoreactive label in granule, periglomerular, and mitral cells. Positive fibers were noted in the external plexiform and granule cell layers, glomeruli, and in the molecular layer of the anterior olfactory nucleus. The cerebral cortex contained calretinin label in nonpyramidal bipolar cells. Cells in the substantia nigra compacta and ventral tegmental area were also calretinin positive as were nigrostriatal and mesolimbic projections (caudate-putamen, nucleus accumbens). In the hippocampus, interneurons were stained in all the subfields of the CA1-CA4 regions. In the thalamus, many positive cells were observed in the periventricular, reticular, lateral habenula, and reunions nuclei. Calretinin immunoreactive cells were particularly abundant in the lateral mamillary and septofimbrial nuclei. Several fiber tracts were also revealed, i.e., the lateral olfactory tract, mamillothalamic tract, fasciculus retroflexus, optic tract, and stria medullaris. These results demonstrate a distinct distribution of calretinin within cell bodies and fibers.

Metabolic mapping of the effects of intravenous methamphetamine administration in freely moving rats

The 2-[14C]deoxyglucose method was used to examine the effects of acute intravenous administration of methamphetamine (0.5-2.5 mg/kg) on rates of local cerebral glucose utilization in freely-moving rats. These effects were correlated with the effects of methamphetamine on locomotor activity assessed simultaneously in the same animals. Methamphetamine administration resulted in widespread dose-dependent increases in glucose utilization within structures of the extrapyramidal motor system. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, entopeduncular nucleus, subthalamic nucleus, and the lateral cerebellar cortex. In contrast, within the limbic system alterations in metabolic activity were smaller and more selective. Glucose utilization was increased in the nucleus accumbens at all doses tested, but alterations in glucose utilization in the ventral tegmental area, amygdala, and anterior cingulate were observed only at the highest doses of methamphetamine tested. Significant increases in rates of glucose metabolism were also found in the substantia nigra compacta and in the median and dorsal raphe nuclei. Dopamine and serotonin are depleted in these regions, as well as in the ventral tegmental area where glucose utilization was also increased, following chronic treatment with high doses of methamphetamine. These changes in glucose utilization may be indicative of disturbances in the biochemical processes involved in the neurotoxic effects of methamphetamine.

Dose-dependent destruction of the coeruleus-cortical and nigral-striatal projections by MPTP

In order to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces neuronal death or the loss of tyrosine hydroxylase (TH) immunoreactivity, 4 catecholaminergic nuclei in the mouse: substantia nigra compacta (SNc), locus coeruleus (LC), ventral tegmental area (VTA) and the A13 nucleus in the hypothalamus were quantitatively examined. Serial sections were taken through the restrocaudal extent of each nucleus: alternate sections were incubated with TH antiserum and reacted with an immunoperoxidase technique while the alternate set was Nissl stained. Counts and 3 dimensional reconstructions of TH reactive somata were made for each nucleus for saline-treated controls and mice treated with different doses of MPTP (37.5, 75, 150 and 300 mg/kg). TH-positive neurons were counted along with their counterparts on the Nissl-stained alternative sections to both identify the catecholaminergic neurons and to measure their destruction. Concentrations of striatal dopamine and cortical norepinephrine were measured for all dosages of MPTP in order to determine the relationship between dosage, target tissue neurotransmitter concentration and neuronal destruction. By 20 days after MPTP injection there was a dose-dependent random loss of TH-immunoreactive neurons that was almost identical in all 4 nuclei examined. Analysis of the Nissl versus TH cell counts revealed that MPTP resulted in neuronal destruction in the SNc and the LC rather than just a loss of TH immunoreactivity. There was no difference in sensitivity to MPTP between the SNc and the LC. Decreases in cortical norepinephrine concentrations were about one third of the decreases of LC neuronal counts for all MPTP doses; while decreases in striatal dopamine and SNc cell loss was similar to the LC for the two lower doses of MPTP but for the higher doses, the relationship approached or exceeded a one to one ratio. Hence estimates of neuronal death based upon target tissue transmitter concentrations could not be made using the same relationship for SNc and the LC catecholaminergic neurons and use of the same relationship for higher MPTP dosages results in an underestimate of LC neuronal destruction relative to that in the SNc.

Afferent and efferent connections of the laterodorsal tegmental nucleus in the rat

The connections of the laterodorsal tegmental nucleus (LDTg) have been investigated using anterograde and retrograde lectin tracers with immunocytochemical detection. Inputs to LDTg were found from frontal cortex, diagonal band, preoptic areas, lateral hypothalamus, lateral mamillary nucleus, lateral habenula; the interpeduncular nucleus, ventral tegmental area, substantia nigra and retrorubral fields; the medial terminal nucleus, interstitial nucleus, supraoculomotor central grey, medial pretectum, nucleus of the posterior commissure, paramedian pontine reticular formation, paraabducens and paratrochlear region; the parabrachial nuclei and nucleus of the tractus solitarius. Terminal labelling from PHA-L injections of LDTg was found in infralimbic, cingulate and hippocampal cortex, lateral septum, septofimbrial and triangular nuclei, horizontal limb of diagonal band and preoptic areas; in the anterior, mediodorsal, reuniens, centrolateral, parafascicular, paraventricular and laterodorsal thalamic nuclei, rostral reticular thalamic nucleus, and zona incerta; the lateral habenula and the lateral hypothalamus. A number of brainstem structures apparently associated with visual functions were also innervated, mainly the superior colliculus, medial pretectum, medial terminal nucleus, paramedian pontine reticular formation, inferior olive, supraoculomotor, paraabducens and supragenual regions, prepositus hypoglossi and nucleus of the posterior commissure. Also innervated were substantia nigra compacta, ventral tegmental area, interfascicular nucleus, interpeduncular nucleus, dorsal and medial raphe, pedunculopontine tegmental region, parabrachial nuclei, and nucleus of the tractus solitarius. These findings suggest the LDTg to be a highly differentiated part of the ascending “reticular activating” system, concerned not only with specific cortical and thalamic regions, especially those associated with the limbic system, but also with the basal ganglia, and visual (particularly oculomotor) mechanisms. Additional links with the habenula-interpeduncular system are discussed in this context.

The influence of striatum on the substantia nigra: A study using the spreading depression technique

Effects of changes in striatal neurone activity on substantia nigra (SN) unit activity were studied in rats. Striatal changes were produced by the spreading depression (STSD) induced by perfusing the head of Striatum with 0.06 M KC1 via a push-pull cannula. In the medial part (caudate) striatal neurones are silent, with the arrival of STSD they exhibit a brief excitation coinciding with the onset of a slow wave of depolarisation in the extracellular steady potential. In the lateral part (putamen) striatal neurones are active, they undergo an arrest of their spontaneous activity for about 1 minute following the brief excitation. Antidromic activation of SN reticulata (SNr) neurones was attempted from the superior colliculus (SC). The majority of the 54 SNr neurones (96%) exhibited changes in firing rate during STSD. Ten neurones underwent brief single or repetitive changes of the same duration as the brief striatal excitation. Eight presented an initial brief change of activity followed by a longer duration inverse change in firing rate. Eighteen exhibited multiple brief changes followed by or superimposed on a long lasting decrease of firing rate and 50% of them were nigrotectal neurones. Sixteen neurones presented long duration biphasic changes in firing rate. Two SNr neurones and the 12 substantia nigra compacta (SNc) neurones studied were unaffected. Some neurones received both inhibitory and facilitatory striatal controls. In total thirty-nine neurones were inhibited and 47 facilitated, the origin of these effects from caudate and putamen are discussed. The excitatory action may be due to either a direct excitatory pathway or to a relayed effect of the inhibitory GABAergic pathway.

The effect of fetal mesencephalon implants on primate MPTP-induced parkinsonism

Parkinsonism or hemiparkinsonism was induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in four rhesus monkeys, which then received homologous fetal mesencephalon implants into the caudate nuclei. Cavities were prepared in the medial caudate nucleus 2 to 5 weeks before the fetal grafts were implanted. Control studies were conducted in unoperated MPTP-treated animals. Significant behavioral improvement, which occurred within weeks of implantation of fetal mesencephalon, was sustained for up to 7 months. No recovery was seen in the unoperated control animals. Histological examination revealed numerous surviving tyrosine hydroxylase (TH)-immunoreactive cell bodies. In addition to the graft, abundant TH-immunoreactive fibers were observed in the host caudate nucleus ventral to the region of the implanted and the nonimplanted cavities. Since TH-immunoreactive cell bodies of the substantia nigra compacta (A-9 cells) were destroyed by MPTP treatment and the ventral tegmental area (A-10) remained intact, it is concluded that sprouting of remaining host dopaminergic fibers occurs. These newly formed fibers appeared to emanate from the mesolimbic projection to the striatum. It is likely that the newly sprouted dopaminergic fibers account for the motor improvement elicited by precavitation and fetal mesencephalon implantation. These results suggest that the mechanism of recovery of parkinsonian primates after implantation of fetal dopaminergic tissue into the caudate nucleus is by stimulation of sprouting from host neurons. They also suggest that, with identification of the factors responsible for the formation of the new dopaminergic neuronal processes and with further development, tissue implantation may be an effective therapy for Parkinson's disease in humans.

Effect of vigabatrin on excitatory amino acid and GABA contents in rats : Paavo J. Riekkinen 1, Toivo Halonen 1,2, and Asla Pitkänen 11Department of Neurology, University of Kuopio, SF-70211 Kuopio and 2Vaajasalo Hospital, Kortejoki, SF-71130 Kuopio, Finland

Endogenous excitotoxins have been implicated in the degeneration of dopaminergic neurons in the substantia nigra compacta of patients with Parkinson's disease. One such agent quinolinic acid is an endogenous excitatory amino acid receptor agonist. This study examined whether an increased level of endogenous kynurenic acid, an excitatory amino acid receptor antagonist, can protect nigrostriatal dopamine neurons against quinolinic acid-induced excitotoxic damage.Nigral infusion of quinolinic acid (60 nmoles) or N-methyl-d- aspartate (15 nmoles) produced a significant depletion in striatal tyrosine hydroxylase activity, a biochemical marker for dopaminergic neurons. Three hours following the intraventricular infusion of nicotinylalanine (5.6 nmoles), an agent that inhibits kynureninase and kynurenine hydroxylase activity, when combined with kynurenine (450 mg/kg i.p.), the precursor of kynurenic acid, and probenecid (200 mg/kg i.p.), an inhibitor of organic acid transport, the kynurenic acid in the whole brain and substantia nigra was increased 3.3-fold and 1.5-fold respectively when compared to rats that received saline, probenecid and kynurenine. This elevation in endogenous kynurenic acid prevented the quinolinic acid-induced reduction in striatal tyrosine hydroxylase. However, 9 h following the administration of nicotinylalanine with kynurenine and probenecid, a time when whole brain kynurenic acid levels had decreased 12-fold, quinolinic acid injections produced a significant depletion in striatal tyrosine hydroxylase. Intranigral infusion of quinolinic acid in rats that received saline with kynurenine and probenecid resulted in a significant depletion of ipsilateral striatal tyrosine hydroxylase. Administration of nicotinylalanine in combination with kynurenine and probenecid also blocked N-methyl-d-aspartate-induced depletion of tyrosine hydroxylase. Tyrosine hydroxylase immunohistochemical assessment of the substantia nigra confirmed quinolinic acid-induced neuronal cell loss and the ability of nicotinylalanine in combination with kynurenine and probenecid to protect neurons from quinolinic acid-induced toxicity.The present study demonstrates that increases in endogenous kynurenic acid can prevent the loss of nigrostriatal dopaminergic neurons resulting from a focal infusion of quinolinic acid or N-methyl-d-aspartate. The strategy of neuronal protection by increasing the brain kynurenic acid may be useful in retarding cell loss in Parkinson's disease and other neurodegenerative diseases where excitotoxic mechanisms have been implicated.

The mechanism of amphetamine-induced inhibition of rat substantia nigra compacta neurones investigated with intracellular recording in vitro.

1. The effects of (+)-amphetamine (1-300 microM) applied by superfusion, on substantia nigra zona compacta neurones were studied in slices of the rat mesencephalon with intracellular recording techniques (current and voltage clamp mode). 2. Amphetamine inhibited the action potential discharge, hyperpolarized the cells and increased the membrane conductance. Under voltage clamp it produced an outward current. 3. The amphetamine outward current reversed at potentials negative to -100 mV (2.5 mM extracellular potassium) and was reduced by barium, (1 mM) suggesting an increased potassium conductance. 4. In slices treated with tetrodotoxin and calcium-free solution and added cobalt, amphetamine was still effective. 5. (-)-Sulpiride, (1 microM) a D2 antagonist, blocked the effects of both amphetamine and dopamine. 6. In slices treated for more than 3 h with 30 microM alpha-methyl-DL-tyrosine, an agent known to block the synthesis of dopamine, the action of amphetamine was attenuated, while dopamine was still effective. 7. Responses to applied dopamine were potentiated by cocaine (10 microM) but unaffected by amphetamine (1-3 microM). 8. It is suggested that the inhibition of substantia nigra compacta neurones by amphetamine is mainly due to the release of endogenous dopamine.

Substance P-like immunoreactivity in brains with pathological features of Parkinson's and Alzheimer's diseases

Substance P is found in both the basal ganglia and cerebral cortex in mammalian brain. In the present study postmortem concentrations of substance P-like immunoreactivity (SP-LI) were measured in the globus pallidus, substantia nigra and 22 cortical regions in a group of demented patients with neuropathological features of both Parkinson's disease (PD) and Alzheimer's disease (AD), and from neurologically normal controls. There were no significant changes in the globus pallidus but concentrations were significantly reduced by 44% in the substantia nigra compacta in the PD patients. In cerebral cortex small (20–30%) significant reductions of SP-LI were found in the PD patients in 7 of 22 cortical regions examined. These results are similar to changes found in AD alone and provide further evidence that the dementia of PD is frequently related to the coicidence of PD and AD.

Cholinergic somata and terminals in the rat substantia nigra: an immunocytochemical study with optical and electron microscopic techniques.

The topographical distribution, histochemical characteristics, and anatomical relationships of the cellular elements containing choline acetyltransferase (ChAT) immunoreactivity, demonstrated with specific monoclonal antibodies to ChAT following the unlabelled antibody peroxidase-antiperoxidase (PAP) procedure at the optical and electron microscopic levels, were investigated in the rat substantia nigra (SN). Scarce, large (20-30 microns in maximum soma extent) cholinergic cell bodies and processes were found within the boundaries of the SN, in the borders of the pars compacta and pars reticulata, principally at caudal levels. Occasionally, cholinergic neurons were also found at intermediate levels of the SN, in the borders of the pars reticulata and pars lateralis. Cytologically, these large cells resembled ChAT-positive neurons localized in other areas of the central nervous system (CNS) of the rat--for example, the pontomesencephalotegmental (PMT) cholinergic complex (Ch5-Ch6) and the nucleus basalis of Meynert (nbM) (Ch4). Histochemically, ChAT-positive cells in the SN were characterized by their ability to utilize the reduced cofactor nicotinamide adenine dinucleotide phosphate (NADPH). Identified ChAT-positive neurons in the light microscope were subsequently studied in the electron microscope. All cholinergic neurons in the SN share essentially the same ultrastructural characteristics. The copious cytoplasm was rich in organelles with large lipofuscin granules. The synaptic input onto cell bodies and their dendrites was studied in serial sections. Synaptic contacts onto the perikarya and proximal dendrites were sparse and of asymmetric type. Both symmetric and asymmetric synaptic specializations onto ChAT-positive distal dendrites were detected. Asymmetric synaptic contacts onto cell bodies and dendrites were often defined by the presence of subjunctional dense bodies associated with the postsynaptic membrane. The pattern of the synaptic input to these cells differs strikingly from that onto unlabelled neighboring neurons. The perikarya and dendrites of the latter were characteristically covered with synaptic boutons. Scarce immunoreactive terminals in asymmetric synaptic contact with unlabelled dendritic profiles were also detected in portions of SN compacta with no ChAT-positive cells. Extranigrally located ChAT-positive cells of the PMT cholinergic complex were also examined in the electron microscope for comparison purposes. These cells exhibited, on the basis of their morphology and synaptic input pattern, very similar characteristics to those shown by SN cholinergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Regional localization of the mRNA coding for the neuropeptide cholecystokinin in the rat brain studied by in situ hybridization

The regional localization of mRNA coding for the neuropeptide cholecystokinin (CCK) has been studied in the rat brain by in situ hybridization using a 32P-labelled synthetic 32 mer oligonucleotide. Autoradiograms were quantified using computer-assisted microdensitometry. High levels of hybridization were observed in the neocortex, claustrum, endopiriform nucleus, cingular cortex, amygdala, olfactory bulb, hippocampus, ventral tegmental area, geniculate nucleus, several thalamic nuclei and substantia nigra compacta. Very weak signal was detected in the striatum, the cerebellum and the brainstem. The topographic distribution of CCK neurons observed overlaps in part with that previously described by immunohistochemical techniques. However, some discrepancies were also found, particularly in the thalamus. These results show that in situ hybridization with oligonucleotide probes together with a semiquantitative method described can be used to map the expression of the CCK mRNA in rat brain sections as well as its modification after pharmacological or physiological manipulations.

Somatostatin and neuropeptide Y concentrations in pathologically graded cases of Huntington's disease.

Somatostatin and neuropeptide Y concentrations have previously been reported to be increased in the basal ganglia in Huntington's disease (HD). In the present study we have extended these findings by examining both somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) in cases of HD, which were graded according to the severity of pathological degeneration in the striatum. In addition, we surveyed a large number of subcortical nuclei and cortical regions for alterations. Both SLI and NPYLI were significantly increased about threefold in the caudate, putamen, and the nucleus accumbens. Increases in mild and severe grades were similar, which is consistent with a relative but not absolute sparing of striatal aspiny neurons in which somatostatin and neuropeptide Y are colocalized. Significant increases of NPYLI were also found in the external pallidum, subthalamic nucleus, substantia nigra compacta, claustrum, anterior and dorsomedial thalamus, bed nucleus of the stria terminalis, and locus ceruleus. SLI was significantly increased in the external pallidum, red nucleus, and locus ceruleus. Measurements of both neuropeptides were made in 24 regions of the cerebral cortex. Significant increases in both NPYLI and SLI were found in the frontal cortex (Brodmann areas 6, 8, 9, 10, 11, and 45) and temporal cortex (Brodmann area 21), whereas NPYLI was also increased in Brodmann areas 12, 20-22, 25, and 42. Alterations in the cerebral cortex were as pronounced in cases with mild striatal pathological changes as in those with severe striatal pathological changes. These alterations may occur early in HD and could reflect a selective sparing of somatostatin-neuropeptide Y cortical neurons combined with cortical atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Localization of nigrostriatal dopamine receptor subtypes and adenylate cyclase

Quantitative autoradiography using [ 3H]-SCH 23390, [ 3H]-sulpiride and [ 3H]-forskolin was used to assess the effects of single and combined neurotoxin lesions of the nigrostriatal pathway in the rat brain on dopamine (DA) receptor subtypes and adenylate cyclase (AC), respectively. Ibotenic acid (IA) lesions of the caudate-putamen (CPu) resulted in near total loss of both [ 3H]-SCH 23390 and of [ 3H]-forskolin binding in the ipsilateral CPu and substantia nigra reticulata (SNR). [ 3H]-sulpiride binding in the CPu was only partially removed by this same lesion, and nigral [ 3H]-sulpiride binding was virtually unchanged. 6-Hydroxydopamine (6-OHDA) and IA lesions of the substantia nigra compacta (SNC) did not affect [ 3H]-SCH 23390 or [ 3H]-forskolin binding, but largely removed [ 3H]-sulpiride binding in the SNC. A 6-OHDA lesion of the nigrostriatal pathway followed by an ipsilateral IA injection of the CPu failed to further reduce [ 3H]-sulpiride binding in the CPu. These results demonstrate that postsynaptic DA receptors in the CPu are of both the D1 and D2 variety; however, a portion of D2 receptors in the CPu may be presynaptic on afferent nerve terminals to this structure. D1 receptors in the SNR are presynaptic on striatonigral terminals, whereas the D2 receptors of the SNC are autoreceptors on nigral DA neurons. The existence of presynaptic D2 receptors on nigrostriatal DA-ergic terminals could not be confirmed by this study. Co-localization of D1 receptors and AC occurs in both the CPu and SNR.

Dopamine D-2 auto- and postsynaptic receptors in the nigrostriatal system of the rat brain: localization by quantitative autoradiography with [ 3H]sulpiride

In vitro receptor autoradiography with [ 3H]sulpiride (a selective D-2 antagonist) was used to assess the effect of 6-hydroxydopamine and ibotenic acid lesions of the caudate-putamen and substantia nigra pars compacta on D-2 dopamine receptors in rat brain. A marked reduction in [ 3H]sulpiride binding within the pars compacta of the substantia nigra resulted from lesions of the substantia nigra compacta with either toxin, while substantial reduction in binding within the caudate-putamen followed only ibotenate lesions of that structure. Since (−)sulpiride is a selective D-2 antagonist, these data confirm that autoreceptors on nigral DA neurons are of the D-2 type, while a portion of D-2 receptors in the caudate-putamen are postsynaptic on striatal neurons.

MPP + (1-methyl-4-phenylpyridine) is a neurotoxin to dopamine-, norepinephrine- and serotonin-containing neurons

1-Methyl-4-phenylpyridine (MPP +) is an oxidative metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). MPP + produced local cell death when injected directly into substantia nigra compacta, locus coeruleus, or dorsal and median raphe nuclei of rats. Corresponding significant decreases in dopamine, serotonin and norepinephrine levels were observed in the terminal areas. These observations indicate that MPP + is a non-selective neurotoxin which causes lesions not only in dopaminergic neurons but also in noradrenergic and serotonergic systems following intracranial administration. Selective lesioning of these monoaminergic systems could only be achieved by a stereotaxic injection of MPP + into specific brain regions containing monoamine neurons.

“In vivo” visualization by positron emission tomography of the progressive striatal dopamine receptor damage occuring in MPTP-intoxicated non-human primates

Intravenous administration of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) leads to the progressive development of a model of Parkinson's disease in the primate. The development of damage occuring in the striatal area during MPTP-treatment was followed “in vivo” in a baboon by positron emission tomography (PET). Spiperone labelled with a positron emitter 76Br ( 76Br-BSP) was used for the quantitative “in vivo” imaging of D 2 dopamine receptors. The decrease in the striatal binding of 76Br-BSP measured “in vivo”, after three series of MPTP injections, paralleled the increase in the severity of behavioral symptoms seen immediately after administration of the neurotoxin. At the end of the MPTP-treatment when neurological symptoms were the most important, a 36 % decrease in the 76Br-BSP specific binding was measured. Between the series of MPTP injections a partial recovery in the quantitative measurement of the 76Br-BSP specific binding occuring in the striatum was well correlated with the disappearance of the neurological syndrome. Post-mortem histological and biochemical studies in nigro-striatal anatomical structures of MPTP-intoxicated primates compared with control animals showed a 80 % loss of neuronal cell bodies in the substantia nigra compacta and a 42 % decrease in the density (Bmax) of D 2 receptors (in vitro 3H-spiperone binding). All these results showed that the use of PET and 76Br-BSP allow to follow in a noninvasive way both the degenerative processes and the subsequent partial recovery which occur in dopaminergic striatal receptor function during MPTP-treatment.

Changes in substantia nigra pars reticulata activity following lesions of the substantia nigra pars compacta

Single unit activity of substantia nigra reticulata (SNr) neurons was recorded in normal rats and bilaterally in rats subjected to a unilateral 6-hydroxydopamine lesion of the substantia nigra compacta 2–4 weeks previously. Lesions were assessed by rotational behaviour to apomorphine. In normal rats the majority of neurons (63%) showed a regular firing pattern. Following lesion the percentage of these cells was similar in the SNr contralateral to the lesion but decreased on the lesioned side to 26%, whereas bursting activity developed (37% vs 5% in normal rats). The mean firing rate of reticulata neurons was slightly increased after lesion, but not statistically significant.