Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6-hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration

Systemic administration of the selective D1 agonist, SKF 38393, to rats with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway induces contralateral turning and reduces firing rates of substantia nigra pars reticulata neurons. Previous studies have shown that chronically administered levodopa diminishes the contralateral turning induced by SKF 38393 in these animals. The present study demonstrates that twice daily injections (45-50 mg/kg, i.p.) of levodopa for 19 days also diminishes the effects of SKF 38393 on substantia nigra pars reticulata activity. Concomitant with this change, chronic levodopa injections reversed the lesion-induced supersensitivity of substantia nigra pars reticulata neurons to iontophoresed GABA. Neither of these effects were produced by the continuous infusion of levodopa (90-100 mg/kg/day, i.p. by osmotic pump) for 19 days, a treatment that produces average daily blood levodopa levels similar to those produced by chronic levodopa injection. These results suggest that large variations in circulating levodopa levels in 6-hydroxydopamine lesioned rats may desensitize the behavioral responses to D1 dopamine agonist administration by down-regulating D1 and GABA receptor-mediated mechanisms of basal ganglia output through the substantia nigra pars reticulata.     

Striatonigral projection neurons contain D1 dopamine receptor-activated c-fos

Dopamine receptor agonists which stimulate the D1 receptor have been shown to activate c-fos in the striatum ipsilateral to a 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. In the present study, striatal neurons ipsilateral to a 6-OHDA lesion of the medial forebrain bundle were retrogradely labelled by injection of the fluorescent tracer Fluoro-Gold into the substantia nigra pars reticulata. Five days later, c-fos was induced in the 6-OHDA-denervated striatum by injection of the selective D1 agonist SKF 38393. C-fos-positive nuclei were frequently found in medium-sized striatal cell bodies labelled with Fluoro-Gold. These results indicate that D1 agonists activate c-fos in medium-sized neurons that project to the substantia nigra pars reticulata.     

Spreading of slow cortical rhythms to the basal ganglia output nuclei in rats with nigrostriatal lesions

A high proportion of neurons in the basal ganglia display rhythmic burst firing after chronic nigrostriatal lesions. For instance, the periodic bursts exhibited by certain striatal and subthalamic nucleus neurons in 6-hydroxydopamine-lesioned rats seem to be driven by the approximately 1 Hz high-amplitude rhythm that is prevalent in the cerebral cortex of anaesthetized animals. Because the striatum and subthalamic nucleus are the main afferent structures of the substantia nigra pars reticulata, we examined the possibility that the low-frequency modulations (periodic bursts) that are evident in approximately 50% nigral pars reticulata neurons in the parkinsonian condition were also coupled to this slow cortical rhythm. By recording the frontal cortex field potential simultaneously with single-unit activity in the substantia nigra pars reticulata of anaesthetized rats, we proved the following. (i) The firing of nigral pars reticulata units from sham-lesioned rats is not coupled to the approximately 1 Hz frontal cortex slow oscillation. (ii) Approximately 50% nigral pars reticulata units from 6-hydroxydopamine-lesioned rats oscillate synchronously with the approximately 1 Hz cortical rhythm, with the cortex leading the substantia nigra by approximately 55 ms; the remaining approximately 50% nigral pars reticulata units behave as the units recorded from sham-lesioned rats. (iii) Periodic bursting in nigral pars reticulata units from 6-hydroxydopamine-lesioned rats is disrupted by episodes of desynchronization of cortical field potential activity. Our results strongly support that nigrostriatal lesions promote the spreading of low-frequency cortical rhythms to the substantia nigra pars reticulata and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.     

Convergent Synaptic Input From the Neostriatum and the Subthalamus Onto Identified Nigrothalamic Neurons in the Rat

The two major afferents of the substantia nigra pars reticulata are the subthalamic nucleus and the striatum. Stimulation of these afferents has opposing physiological effects on the output neurons of the substantia nigra pars reticulata. In order to better understand the role of these afferents in the flow of information through the basal ganglia and to better understand the ways in which they might interact, experiments have been performed to test the possibility that single-output neurons of the substantia nigra pars reticulata receive convergent synaptic input from the subthalamic nucleus and the neostriatum. To address this, rats received iontophoretic deposits of the anterograde tracer Phaseolus vulgaris leucoagglutinin in the subthalamic nucleus, injections of the anterograde tracer biocytin in the neostriatum and injections of the retrograde tracer horseradish peroxidase conjugated to wheat-germ agglutinin in the ventral medial nucleus of the thalamus. Following appropriate survival times the animals were perfusion-fixed and sections of the substantia nigra were processed to reveal the transported tracers and prepared for electron microscopy. Light microscopic examination revealed that the substantia nigra contained rich plexuses of anterogradely labelled subthalamic and striatal terminals, as well as many retrogradely labelled nigrothalamic neurons. The anterogradely labelled terminals were often seen apposed to the retrogradely labelled neurons. In the electron microscope the subthalamic terminals were seen to form asymmetrical synaptic contacts (subthalamic type 1) with the identified nigrothalamic neurons as well as unlabelled perikarya and both proximal and distal dendrites. In confirmation of previous findings, the striatal terminals made symmetrical synaptic contact with the nigrothalamic neurons as well as unlabelled neurons. In areas of overlap between the two classes of terminals, identified nigrothalamic neurons and unlabelled nigral neurons were found to receive convergent synaptic input from the subthalamic nucleus and the neostriatum. In addition to the anterogradely labelled subthalamic terminals that formed asymmetrical synaptic specializations, a second, much rarer class was also observed (subthalamic type 2). These terminals were much larger and formed symmetrical synapses; several lines of evidence suggest that they originated not in the subthalamic nucleus but in the globus pallidus. These terminals were found to make synaptic contacts with identified nigrothalamic neurons and non-labelled neurons and to form convergent synaptic contacts with subthalamic type 1 terminals and striatal terminals. It is concluded that the topographical and synaptic organization of the so-called direct (striatum to substantia nigra pars reticulata) and indirect pathways (i.e. pathways involving the subthalamic nucleus andlor the globus pallidus) of information flow through the basal ganglia underlies the inhibition and excitation of the output neurons of the substantia nigra pars reticulata that occur following stimulation of the striatum.     

GM1 ganglioside treatment partially reverses the nigrostriatal dopamine defect in the weaver mutant mouse

The weaver mutation in the mouse is a developmental disorder characterized by cerebellar atrophy as well as decreased numbers of substantia nigra dopaminergic neurons and a striatal dopamine loss. Since the nigrostriatal dopamine loss occurs postnatally, the present study was performed to determine whether early intervention with G_M1 ganglioside could alter the extent of this dopamine loss. Weaver mice that received injections of G_M1 ganglioside (30 mg/kg) daily, beginning at 7–10 days of age, had significantly higher striatal dopamine levels and significantly more tyrosine hydroxylase-positive substantia nigra pars compacta neurons than weaver mice that received only daily saline injections. These results show that G_M1 treatment can alter at least some aspects of this inherited developmental disorder. If the weaver defect is related to a deprivation of trophic support for certain midbrain dopaminergic neurons, the presence of G_M1 may be able to enhance the survival of these neurons.     

The neostriatal mosaic. I. Compartmental organization of projections from the striatum to the substantia nigra in the rat

Combined neuroanatomical techniques were used to examine the organization of the striatal projection to the substantia nigra in the rat. Both double anterograde axonal tracing methods (Phaseolus vulgaris leuco-agglutinin (PHA-L) and 3H-amino acid tract tracing) and double fluorescent retrograde axonal transport tracing methods were used to examine the relationship among striatal neurons projecting to separate areas of the substantia nigra. Additionally, the distributions of retrogradely labeled striatonigral projection neurons were charted relative to the neurochemically distinct striatal "patch" compartment, identified by substance P- or leu-enkephalin-like immunoreactivity, and the complementary "matrix" compartment, identified by somatostatin-like immunoreactive fibers. These studies show two distinct types of organization in the striatonigral projections. One type is topographic in that the mediolateral relationships among these striatal efferent neurons are roughly maintained by their termination patterns in the substantia nigra, while the dorsoventral relationships are inverted. Projections from any part of the striatum, however, are distributed throughout the rostrocaudal axis of the substantia nigra. Despite their general topographic organization, the variable and dispersed nature of such projections from individual striatal loci results in partial overlap of afferent fields from separate striatal areas. The second type of organization is nontopographic and provides a different system for convergence of inputs from separated striatal areas that is superimposed on the rough topographic system. In this other projection system the mediolateral and dorsoventral relationships typical of the topographically ordered system are not maintained and are sometimes reversed. For example, PHA-L injected into the dorsal striatum labels a topographic (inverted relationship) projection to the ventral substantia nigra pars reticulata but also a smaller and separate projection to the dorsal pars reticulata and adjacent pars compacta. Retrograde tracer deposits in the pars compacta label neurons in the ventral striatum (the inverted relationship) but also clusters of neurons in the dorsal striatum. These clusters are in the neurochemically defined patch compartment whereas neurons in the matrix are labeled by injections into the pars reticulata. The dendrites of both retrogradely filled patch and matrix neurons are confined to the compartment containing their cell bodies, suggesting a restriction that would functionally segregate extrinsic striatal afferents shown in other studies to be confined to either patches or matrix.(ABSTRACT TRUNCATED AT 400 WORDS)     

Intranigral GR-113808, a selective 5-HT4 receptor antagonist, attenuates morphine-stimulated dopamine release in the rat striatum

GR-113808, a potent and selective 5-HT₄ receptor antagonist, was infused through a microdialysis probe into the striatum and nucleus accumbens of awake rats, and basal and morphine-stimulated extracellular concentrations of dopamine (DA) were measured in these regions. At 1 and 10 μM GR-113808 did not effect the extracellular concentrations of DA in either region and 100 μM significantly reduced dialysate DA only in the striatum. A subcutaneous dose of 5 mg/kg morphine significantly raised extracellular concentrations of DA in the striatum and nucleus accumbens from 60 to 120 min after injection and the effect was not modified by 10 μM GR-113808 infused through the probe 20 min before and for 60 min after morphine. Bilateral injections of GR-113808 (1, 2.5 and 10 μg/0.5 μl) in the substantia nigra pars compacta did not affect dialysate DA in the striatum, except for a significant increase 120 min after the injection of 10 μg but the highest dose of GR-113808 prevented the increase of striatal DA caused by 5 mg/kg morphine s.c. The results suggest that 5-HT₄ receptors in the substantia nigra modulate the activity of the dopaminergic nigrostriatal system only when the neurons are activated.     

Endogenous dopamine can modulate inhibition of substantia nigra pars reticulata neurons elicited by GABA iontophoresis or striatal stimulation

Previous reports from this laboratory have described an ability of iontophoretically applied dopamine to attenuate the inhibitory effects of iontophoresed GABA on neurons of the substantia nigra pars reticulata. This finding raised the question of whether endogenous dopamine, released from dendrites of neighboring pars compacta dopamine neurons, might act as a neuromodulator which diminishes the inhibition of pars reticulata neurons evoked by either GABA iontophoresis or electrical stimulation of the striatonigral GABAergic pathway. Extracellular, single-unit activity of pars reticulata neurons was recorded in male rats anesthetized with chloral hydrate. In one set of studies, d-amphetamine, a drug reported to release dopamine from nigral dendrites, was administered intravenously (1.6 mg/kg) during regular, intermittent iontophoretic pulses of GABA. As had been previously observed with iontophoresed dopamine, i.v. amphetamine significantly lessened the inhibition of reticulata neurons produced by GABA application. This change was reflected by a decrease in GABA's inhibitory potency by 22% relative to the control level of inhibition achieved prior to amphetamine administration. Amphetamine caused no decreases in GABA's effectiveness, however, in animals that had previously received treatments that depleted or destroyed nigral dopamine stores, i.e., in rats pretreated with reserpine and alpha-methyl-p-tyrosine, or in rats with 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. In a second set of experiments, amphetamine or dopamine was delivered iontophoretically while monitoring the GABA-mediated (bicuculline-reversible) inhibition of reticulata neurons that can be elicited by striatal stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nigral dopaminergic mechanisms in drug-induced circling

Unilateral injections of dopamine into the substantia nigra pars reticulata of pargyline-pretreated rats caused a prolonged, contralateral circling, similar in magnitude to that elicited by the injection of the same amount of dopamine intrastriatally. Contralateral circling was also elicited by the unilateral intranigral injection of amphetamine (after pargyline pretreatment), or by the dopamine agonists ergometrine and SKF 38393. In contrast, bilateral intranigral injection of the dopamine antagonist haloperidol greatly reduced the amphetamine-induced circling of rats with unilateral 6-hydroxydopamine-induced nigrostriatal lesions. These results support the hypothesis that dopaminergic mechanisms in the substantia nigra are involved in motor behavior.     

Substantia nigra opiate receptors on basal ganglia efferents

Many behavioral effects of opiate narcotics and peptides have been linked to effects on dopamine neurons originating in the substantia nigra pars compacta and ventral tegmental area. Selective brain lesions were combined with quantitative autoradiography to determine whether opiate receptors are on dopaminergic somata and/or processes in the substantia nigra pars compacta and ventral tegmental area. 6-Hydroxydopamine lesions that eliminated dopamine neurons produced little change in the pattern or density of [³H]-naloxone binding in the substantia nigra pars compacta or ventral tegmental area. Radiofrequency lesions of the internal capsule or globus pallidus and kainic acid lesions of the striatum markedly decreased [³H]-naloxone binding in the pars compacta and pars reticulata. These results are consistent with a dense distribution of opiate receptors on pallido-nigral and/or striato-nigral fibers and strengthen the likelihood that local effects of opiates on dopamine function in the nigrostriatal pathway are mediated indirectly by actions on nondopaminergic processes.     

Neuronal localization of cannabinoid receptors in the basal ganglia of the rat

Cannabinoid receptors have recently been characterized and localized using a high-affinity radiolabeled cannabinoid analog in section binding assays. In rat brain, the highest receptor densities are in the globus pallidus and substantia nigra pars reticulata. Receptors are also dense in the caudate-putamen. In order to determine the neuronal localization of these receptors, selective lesions of key striatal afferent and efferent systems were made. Striatal neurons and efferent projections were selectively destroyed by unilateral infusion of ibotenic acid into the caudate-putamen. The nigrostriatal pathway was selectively destroyed in another set of animals by infusion of 6-hydroxydopamine into the medial forebrain bundle. After 2- or 4-week survivals, slide-mounted brain sections were incubated with ligands selective for cannabinoid ([3H]CP 55,940), dopamine D1 3H]SCH-23390) and D2 ([3H]raclopride) receptors, and dopamine uptake sites ([3H]GBR-12935). Slides were exposed to 3H-sensitive film. The resulting autoradiography showed ibotenate-induced losses of cannabinoid, D1 and D2 receptors in the caudate-putamen and topographic losses of cannabinoid and D1 receptors in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata at both survivals. Four weeks after medial forebrain bundle lesions (which resulted in amphetamine-induced rotations), there was loss of dopamine uptake sites in the striatum and substantia nigra pars compacta but no change in cannabinoid receptor binding. The data show that cannabinoid receptors in the basal ganglia are neuronally located on striatal projection neurons, including their axons and terminals. Cannabinoid receptors may be co-localized with D1 receptors on striatonigral neurons. Cannabinoid receptors are not localized on dopaminergic nigrostriatal cell bodies or terminals.     

Age-related changes in striatal dopamine activity following nigral muscimol infusions

Microinfusions of muscimol into the substantia nigra pars reticulata produced marked increases in striatal dopamine (DA) utilization without affecting striatal DA concentration in adult rats. In contrast, muscimol increased striatal DA concentration and decreased DA utilization in 16-day-old rat pups. The striatal norepinephrine concentration was not altered in either group. Since previous studies have shown that similar infusions of muscimol are anticonvulsant in adults and proconvulsant in rat pups, our results suggest that the nigrostriatal pathway may play an important role in mediating the nigral effects on seizures.     

A note on the projections of pars compacta neurons within pars reticulata of the substantia nigra in the rat

The ascending projections of pars compacta (SNc) neurons displaced within the pars reticulata (SNr) of the substantia nigra in the rat were examined using a fluorescent retrograde tracing. Following unilateral injections of a tracer into the striatum, SNc cells within the SNr were retrogradely labeled predominantly in the caudal parts, and to a lesser extent in the rostral portions of the nucleus. These nigrostriatal projections arising from the SNc cells within the SNr were only ipsilateral. Injections of a tracer into the nucleus accumbens (Ace) did not produce any labeling of these displaced SNc cells in contrast with cells in the SNc proper. Given that the SNc neurons within the SNr project only to the striatum but not to the Ace, and that they contain dopamine but not cholecystokinin, they might be involved in the motor but not in the limbic function.     

Stability of substantia nigra pars reticulata neuronal discharge rates during dopamine receptor blockade and its possible mechanisms

It is hypothesized that substantia nigra pars reticulata neurons become overactive during a deficit of dopamine transmission. In this study, we examined how acute dopamine receptor blockade (SCH23390 and eticlopride) affects impulse activity of substantia nigra pars reticulata neurons and their response to iontophoretic gamma-amino-n-butyric acid in awake, unrestrained rats. No changes in discharge rate were found during complete dopamine receptor blockade, but these neurons showed a diminished response to gamma-amino-n-butyric acid, suggesting gamma-amino-n-butyric acid receptor hyposensitivity. This may result from tonic increase in gamma-amino-n-butyric acid input from the striatum and globus pallidus, which are activated during dopamine receptor blockade. As substantia nigra pars reticulata neurons are autoactive and resistant to tonic increases in gamma-amino-n-butyric acid input, changes in their responsiveness to phasic gamma-amino-n-butyric acid inputs, not tonic increase discharge rate, may underlie movement disturbance following dopamine deficit.     

Effects of D1 and D2 dopamine receptor stimulation on the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats: D1/D2 coactivation induces potentiated responses

Extracellular single unit recording techniques were used to compare the effects of selective and non-selective dopamine agonists on substantia nigra pars reticulata activity in rats with 6-hydroxydopamine induced lesions of the nigrostriatal dopamine pathway. As previously shown, apomorphine (0.32 mg/kg), a dopamine agonist that interacts with both D1 and D2 dopamine receptor subtypes, produced consistent inhibitions of substantia nigra pars reticulata activity in these animals. The D1-receptor agonist, SKF 38393 (RS-SKF 38393, 10 mg/kg), also induced significant inhibitions in the activity of these neurons in 6-hydroxydopamine lesioned rats, although less consistently than did apomorphine. The effects of SKF 38393 were reversed by the D1-antagonist, SCH 23390. The D2 selective agonist quinpirole was considerably less effective than apomorphine at inhibiting substantia nigra pars reticulata activity at doses up to 1 mg/kg. Since comparable experiments have shown that quinpirole is as effective as apomorphine at producing dopamine D2-autoreceptor-mediated effects on dopamine neuron activity, quinpirole's lack of efficacy in the present study relative to that of apomorphine does not appear to be related to differences in relative potency for central D2-receptors using this route of administration. Rather, the relative effectiveness of SKF 38393 on pars reticulata activity suggests that selective stimulation of D1-receptors is at least, if not more, efficacious than selective stimulation of D2-receptors at inducing alterations in the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats. The simultaneous stimulation of both receptors, however, was considerably more effective than selective stimulation of either receptor subtype: doses of SKF 38393 and quinpirole which had no significant effect on nigral activity when administered alone brought about marked inhibition of the firing of these cells when administered simultaneously. No such inhibition was seen when the inactive enantiomer, S-SKF 38393, was substituted for the racemic form of SKF 38393 in this protocol. These observations in 6-hydroxydopamine lesioned rats support other recent findings indicating that the two dopamine receptor subtypes can interact in a synergistic way to affect basal ganglia output.     

Single unit responses of substantia nigra pars reticula neurons to apomorphine: Effects of striatal lesions and anesthesia

Many of the behavioral consequences of dopamine system activation are thought to be mediated by substantia nigra pars reticulata output pathways. Extracellular, single unit recording studies were conducted to determine how i.v. administration of the dopamine agonist, apomorphine, affects the activity of these pars reticulata neurons. Results revealed that a 320 μg/kg dose of the drug, considered sufficient to stimulate striatal postsynaptic dopamine receptors, caused affinity variable changes in reticulata cell firing. Cells exhibited increases, decreases, or no changes in firing. Many cells also displayed marked minute to minute changes in firing. This non-uniform pattern of responses was not related to state of consciousness since similar responses were observed in both chloral hydrate-anesthetized as well as conscious, paralyzed rats. Both the increases and decreases could be reversed by subsequent administration of haloperidol. The variable responses to apomorphine were reduced but not totally prevented by striatal kainic acid lesions, suggesting that changes in striatonigral transmission may account for some but not all of the firing changes which were observed. A lower dose of apomorphine (20 μg/kg), thought to act primarily at dopamine cell autoreceptors, had little effect on reticula cell firing and did not modify the variable responses normally observed after the higher dose. These results contrast strikingly with the consistent excitatory responses to apomorphine which have previously been observed in the globus pallidus and suggest that complex or multiple indirect effects of the drug may contribute to the varied reticulata responses.     

A Single Intramesencephalic Injection of Brain-Derived Neurotrophic Factor Induces Persistent Rotational Asymmetry in Rats

Brain-derived neurotrophic factor (BDNF) is expressed in dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the ventral tegmental area and provides trophic support for these neurons in vitro. To study the effects of BDNF on the nigrostriatal dopaminergic system in vivo, we administered a single, unilateral injection of BDNF into the medial SNpc of rats and evaluated rotational behavior, striatal levels of dopamine and metabolites, and number of dopaminergic neurons in the SNpc. We found that a single injection of 2 or 3 μg of BDNF, but not of vehicle, caused a persistent increase in the net number of amphetamine-induced rotations/min contraversive to the site of injection. The pattern of rotation is consistent with increased activity of the nigrostriatal dopaminergic system on the side of injection. The amphetamine-induced contraversive rotation could be blocked by administration of the dopaminergic antagonist haloperidol. Apomorphine, a direct-acting dopaminergic agonist, did not induce rotation. Levels of dopamine in the striatum and number of dopaminergic neurons in the SNpc were similar in BDNF- and vehicle-treated animals. The increase in contraversive rotations persisted for up to 12 months after a single injection of BDNF.     

The effects of intranigral GABA and dynorphin A injections on striatal dopamine and GABA release: Evidence that dopamine provides inhibitory regulation of striatal GABA neurons via D2 receptors

The effects of injections of γ-aminobutyric acid (GABA) and dynorphin A into the substantia nigra, pars reticulata on the levels of extracellular dopamine (DA) and GABA in the ipsilateral striatum of halothane-anaesthetized rats were studied using microdialysis. The effects of intranigral injections of substance P and neurokinin A were also studied. Intranigral GABA (300 nmol) or dynorphin A (0.5 nmol) injections produced a simultaneous decrease in DA and increase in GABA levels, while intranigral substance P (0.07 nmol) or neurokinin A (0.09 nmol) injections produced an increase in DA but had no effect on GABA levels. DA agnonists, apomorphine (D₁/D₂), SKF 38393 (D₁) and pergolide (D₂) were applied locally by perfusing them through the microdialysis probe, each at a concentration of 10⁻⁵ M. All 3 agonists decreased the levels of DA in the striatum. However, while apomorphine and SKF 38393 increased, pergolide decreased the levels of GABA in the striatum. The increase in striatal GABA produced by intranigral injections of GABA (300 nmol) was reversed by local perfusion with pergolide (10⁻⁵ M), but was not reversed by local perfusion with SKF 38393 (10⁻⁵ M). These findings suggest that D₁ and D₂ receptors differentially regulate striatal GABA release, and are stimulatory and inhibitory, respectively. Furthermore, it is suggested that nigrostriatal DA functions as an inhibitory modulator of striatal GABA neurons, acting via D₂ receptors.     

Angiotensin II receptor binding associated with nigrostriatal dopaminergic neurons in human basal ganglia

In the human brain, receptor binding sites for angiotensin are found in the striatum and in the substantia nigra pars compacta overlying dopamine-containing cell bodies. In contrast, angiotensin-converting enzyme occurs in the substantia nigra pars reticulata and is enriched in the striosomes of the striatum. In this study, using quantitative in vitro autoradiography, we demonstrate decreased angiotensin receptor binding in the substantia nigra and striatum of postmortem brains from patients with Parkinson's disease. In the same brains the density of binding to angiotensin-converting enzyme shows no consistent change. We propose, from these results, that angiotensin receptors in the striatum are located presynaptically on dopaminergic terminals projecting from the substantia nigra. In contrast, the results support previous studies in rats demonstrating that angiotensin-converting enzyme is associated with striatal neurons projecting to the substantia nigra pars reticulata. These findings raise the possibility that newly emerging drugs that interact with the angiotensin system, particularly converting enzyme inhibitors and new nonpeptide angiotensin receptor blockers, may modulate the brain dopamine system.     

Microinjections of Sch-23390 into the ventral tegmental area and substantia nigra pars reticulata attenuate the development of sensitization to the locomotor activating effects of systematic amphetamine

Pre-exposure of rats to systemic injections ofd-amphetamine sulfate in the presence of bilateral injections of Sch-23390 (0.5 or 1.0 μg/side) into the ventral tegmental area (VTA) attenuated the acute locomotor effects of amphetamine and blocked the development of sensitization to amphetamine in a test when only amphetamine was administered, in a dose-dependent manner. Similar, but less potent, effects were observed following injections into substantia nigra pars reticulata. These findings suggest that dopamine released from somatodendritic regions brings about changes in local circuitry in the VTA that underlie the development of sensitization to amphetamine, and that Sch-23390 acts at D₁ receptors in these regions to block these changes.