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Changes in the control of arm position, movement, and thalamic discharge during local inactivation in the globus pallidus of the monkey.

1. To examine the effect of disruption of basal ganglia output on limb stability and movement, muscimol was injected into the internal globus pallidus (GPi) of monkeys trained to make arm movements to visible or remembered targets in a two-dimensional workspace. 2. Injections of as little as 0.25 micrograms muscimol at GPi sites at which pallidal neurons with arm movement activity had been recorded were followed by drift of the contralateral arm within < 10 min. Drift was usually in the flexor direction. Injections at a few sites in or near the external pallidal segment sometimes were followed by extensor drift. 3. Drift was active (accompanied by activation of agonist muscles), but could be overcome by the animal, resulting in an oscillating movement off and on the required position. 4. The pallidal-receiving (PR) area of the thalamus was identified by recording the response of thalamic neurons to stimulation in the globus pallidus. The activity of 15 neurons identified as PR cells (n = 6) or within the PR region was recorded both before and after injection of muscimol into GPi. After the injection, the tonic discharge increased during the hold period in 47% of the cells studied. When postural drift also occurred, there was a close temporal correlation between the postinjection time at which drift occurred and the time at which the tonic discharge rate increased in thalamic neurons that were clearly related to arm movement. 5. The peak velocity of arm movements to visible or remembered visual target locations was decreased after injection of muscimol into GPi, sometimes with an increase in movement time. 6. The firing rate of PR thalamic neurons after injection of muscimol was also increased during the perimovement period. Because of the increase in the tonic discharge rate, however, the phasic movement-related change in activity could stay the same or even decrease. Postinjection changes in this movement-related phasic activity, however, were not necessarily coincident with changes in peak movement velocity. 7. Changes in reaction time were variable after injection of muscimol. In some cases it was increased, and in others decreased. The time of onset of phasic movement-related changes in the activity of PR neurons studied was not altered by the injection. 8. Our data indicate that the tonic inhibitory output of GPi, in particular to the cortical motor areas, is especially important in the maintenance of postural stability. In the absence of normal pallidal output, desired limb position can be achieved on the basis of either current or prior visual cues, but targeted movements are slowed.

Animals↗

A horseradish peroxidase study of afferent connections of the globus pallidus in Macaca mulatta.

The high tonic discharge rates of globus pallidus neurons in awake monkeys suggest that these neurons may receive some potent excitatory input. Because most current electrophysiological evidence suggests that the major described pallidal afferent systems from the neostriatum are primarily inhibitory, we used retrograde transport of horseradish peroxidase (HRP) to identify possible additional sources of pallidal afferent fibers. The appropriate location was determined before HRP injection by mapping the characteristic high frequency discharge of single pallidal units in awake animals. In animals with injections confined to the internal pallidal segment, retrograde label was seen in neurons of the pedunculopontine nucleus, dorsal raphe nucleus, substantia nigra, caudate, putamen, subthalamic nucleus, parafascicular nucleus, zona incerta, medial and lateral subthalamic tegmentum, parabrachial nuclei, and locus coeruleus. An injection involving the external pallidal segment and the putamen as well resulted in additional labeling of cells in centromedian nucleus, pulvinar, and the ventromedial thalamus.

Afferent Pathways↗

In vivo effects of local activation and blockade of 5-HT1B receptors on globus pallidus neuronal spiking.

Several morphological works have shown that the globus pallidus (GP) contains the highest density of 5-HT1B receptors within the telencephalon. However, the role of these receptors in the spiking of GP neurons in vivo is unknown. In the present work, we use single-unit extracellular recordings in the anesthetized rat to analyze changes in the firing rate of GP neurons evoked by local activation and blockade of 5-HT1B receptors. Intrapallidal administration of serotonin, or the serotonin uptake inhibitor fluoxetine, predominantly produced an excitatory effect in the basal firing rate of GP neurons. The 5-HT1B receptor agonist, L-694,247, caused a dose-dependent excitatory effect on most pallidal neurons tested. Blockade of 5-HT1B receptors by intrapallidal application of methiothepin predominantly caused inhibition in GP neurons firing rate. Moreover, methiothepin diminished the excitatory effect evoked by L-694,247. Furthermore, local serotonin did not evoke significant changes in the basal firing rate of GP neurons in unilateral striatal lesioned rats. Taken all together, these results suggest that serotonin 5-HT1B receptors significantly contribute to the control of spiking of the rat GP neurons, and that the 5-HT1B receptors exerting this control are most likely localized in the striato-pallidal pathway.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Glucose-sensitive neurons of the globus pallidus: I. Neurochemical characteristics.

The lateral hypothalamic area (LHA) and globus pallidus (GP) are basically involved in the regulation of feeding and metabolic processes. In the LHA, glucose-sensitive (GS) neurons were described: their activity was found to be specifically suppressed by electrophoretic application of glucose, and these neurons appeared to be also influenced by various feeding-associated neurochemical signals. The main goal of the present experiments was to examine whether similar GS neurons exist in the GP. In addition, neurochemical attributes of the cells were also tested. In anesthetized rats and anesthetized or awake monkeys, single-neuron activity of the GP was recorded by means of carbon fiber multibarreled microelectrodes and the effects of glucose, glutamate (Gt), GABA, dopamine (DA), noradrenaline (NA) and acetylcholine (Ach) were studied. In both the rat and monkey GP, approximately 12% of the neurons examined responded, with inhibition, to glucose. GP neurons, in a high proportion, were also inhibited by GABA and NA. After application of Gt, DA, or Ach, activity increase or decrease occurred. GS neurons exhibited remarkable sensitivity to these neurochemicals previously identified as neurotransmitters of the complex pallidal, extrapyramidal-limbic neuron loops. The results, along with previous data, indicate that GS cells of the GP, while possessing complex neurochemical characteristics, may belong to a hierarchically organized central glucose-monitoring system essential in the regulation of feeding.

Animals↗

Electron microscopic analysis of the synaptic organization of the globus pallidus in the cat.

The synaptic organization of the feline globus pallidus (GP) was studied electron microscopically. The axon terminals were classified into five types on the basis of the size and shape of synaptic vesicles and the type of postsynaptic differentiations. Type I and II axon terminals were characterized by large, pleomorphic vesicles and by a symmetric and an asymmetric synaptic contact, respectively. Type III and IV axon terminals were characterized by small, pleomorphic vesicles and by a symmetric and an asymmetric synaptic contact, respectively. Type V axon terminals were characterized by elongated and large round vesicles and by a symmetric synaptic contact. The origins of these terminals were determined by a combined degeneration and HRP tracing technique. Following injections of HRP into the caudate nucleus or electrolytic lesions in this nucleus, type I terminals were anterogradely labeled with HRP or degenerated, respectively. Although type III, IV, and V terminals were labeled with HRP after HRP injections into the subthalamic nuclear region, only type IV and V terminals degenerated after lesions in that area. Type II terminals did not show any alterations following such treatment. These results suggest that type I terminals originate from the caudate nucleus, that type IV and V terminals come from the subthalamic nucleus or caudal to it, and that type III terminals are the terminals of intrinsic axon collaterals of GP neurons which send axons to the subthalamic nucleus. Occasionally convergence of different kinds of axon terminals on the same GP neuron was also observed. These terminals originated from the caudate nucleus and the subthalamic nucleus or caudal to it.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Selective innervation of neostriatal interneurons by a subclass of neuron in the globus pallidus of the rat.

A subpopulation of neurons in the globus pallidus projects to the neostriatum, which is the major recipient of afferent information to the basal ganglia. Given the moderate nature of this projection, we hypothesized that the pallidostriatal projection might exert indirect but powerful control over principal neuron activity by targeting interneurons, which comprise only a small percentage of neostriatal neurons. This was tested by the juxtacellular labeling and recording of pallidal neurons in combination with immunolabeling of postsynaptic neurons. In addition to innervating the subthalamic nucleus and output nuclei, 6 of 23 labeled pallidal neurons projected to the neostriatum. Both the firing characteristics and the extent of the axonal arborization in the neostriatum were variable. However, light and electron microscopic analysis of five pallidostriatal neurons revealed that each neuron selectively innervated neostriatal interneurons. A large proportion of the boutons of an individual axon (19-66%) made contact with parvalbumin-immunoreactive interneurons. An individual parvalbumin-immunoreactive neuron (n = 27) was apposed on average by 6.7 boutons (SD = 6.1) from a single pallidal axon (n = 2). Individual pallidostriatal boutons typically possessed more than one symmetrical synaptic specialization. In addition, 3-32% of boutons of axons from four of five pallidal neurons contacted nitric oxide synthase-immunoreactive neurons. Descending collaterals of pallidostriatal neurons were also found to make synaptic contact with dopaminergic and GABAergic neurons of the substantia nigra. These data imply that during periods of cortical activation, individual pallidal neurons may influence the activity of GABAergic interneurons of the neostriatum (which are involved in feed-forward inhibition and synchronization of principle neuron activity) while simultaneously patterning neuronal activity in basal ganglia downstream of the neostriatum.

Action Potentials↗

Glutamic acid decarboxylase 67 mRNA regulation in two globus pallidus neuron populations by dopamine and the subthalamic nucleus.

The globus pallidus (GP) consists of two neuron populations, distinguished according to their immunoreactivity for parvalbumin (PV). The PV-immunoreactive (PV+) neurons project preferentially to "downstream" targets such as the subthalamic and entopeduncular nuclei, whereas neurons lacking PV (PV- neurons) project preferentially to the striatum, suggesting a role for PV- cells in feedback to striatal neurons. Although dopamine D2 antagonist administration induces immediate early gene expression preferentially in PV- GP neurons, little is known about long-term regulation of PV- versus PV+ GP neurons. Nigral 6-hydroxydopamine (6-OHDA) lesions or repeated D2-class antagonist injections have been shown to increase pallidal expression of glutamate decarboxylase (GAD(67) isoform) mRNA. This increase in GAD(67) is believed to be secondary to activation of excitatory subthalamopallidal projections. The current study examined the effects of subthalamic nucleus (STN) lesion on 6-OHDA- or repeated D2 antagonist-induced changes in GP GAD(67) mRNA expression in PV+ and PV- neurons. Five or 21 d after nigral 6-OHDA injections or after 3, 7, or 21 d of D2 antagonist administration, GAD(67) mRNA increased in both the PV- and PV+ GP neurons, but the magnitude of the increase was significantly greater in PV- neurons. By contrast, STN lesion resulted in declines in GAD(67) mRNA in both cell populations, with the decreases in PV+ neurons exceeding those in PV- neurons. Furthermore, STN lesion completely blocked 6-OHDA- or D2 antagonist-induced GAD(67) mRNA increases in PV+ cells but only partly offset the GAD(67) mRNA increase in PV- pallidal neurons. Thus, the PV+ and PV- neurons are influenced in qualitatively similar ways by dopamine and the STN, but these cell types exhibit contrasting degrees of regulation by the dopaminergic and STN perturbations. This pattern of results has implications for pallidal control of striatal versus downstream basal ganglia nuclei.

Animals↗

Dopamine D4 receptor-induced postsynaptic inhibition of GABAergic currents in mouse globus pallidus neurons.

Dopamine D4 receptors (D4R) are localized in the globus pallidus (GP), but their function remains unknown. In contrast, dopamine D2 receptor activation hyperpolarizes medium spiny neurons projecting from the striatum to the GP and inhibits GABA release. However, using slice preparations from D2R-deficient [D2 knock-out (D2KO)] mice, we found that dopamine inhibited GABA(A)-receptor-mediated currents in GP neurons. The paired-pulse ratio was statistically unchanged after dopamine application but was significantly elevated in D2KO wild-type littermates (WT). Furthermore, in D2KO mice, outward currents elicited by iontophoretically applied GABA were suppressed by dopamine. Dopamine (30 microm) decreased the amplitude of miniature IPSCs in both WT and D2KO mice, but the decrease in the frequency was observed only in the former but not significantly in the latter. Dopamine-induced suppression of IPSCs was blocked by selective D4R antagonists (clozapine or 3-[4-(4-iodophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride), and a D4R-selective agonist N-[[4-(2-cyanophenyl)-1-piperazinyl]methyl]-3-methyl-benzamide reversibly and dose-dependently suppressed IPSCs, whereas agonists [SKF38,393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride) or (+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol] or antagonists [SCH23,390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) or sulpiride] of other receptor subtypes had little effect. In GP neurons from D4R-deficient mice, dopamine-induced inhibition of GABAergic outward currents was undetectable. D4R activation suppressed the activity of protein kinase A in GP neurons, resulting in a decrease in the amplitude of GABAergic IPSCs. These findings showed that postsynaptic activation of D4R on the GP neurons reduces GABAergic currents through the suppression of PKA activity.

Animals↗

A presynaptic action of dopamine on globus pallidus afferents to substantia nigra in the rat.

Dopamine applied iontophoretically onto substantia nigra and adjacent reticular formation units, changed the pattern of response evoked in these cells by stimulation of the globus pallidus. This change was reversible and was sensitive to iontophoretically applied dopamine. It is proposed that this effect is brought about by an interaction of dopamine with dopamine receptors located on afferent fibres coming from the globus pallidus.

Acetylcholine↗

A high-resolution fast spin-echo inversion-recovery sequence for preoperative localization of the internal globus pallidus.

A fast spin-echo inversion-recovery (FSE-IR) sequence is described for its utility regarding surgical planning for patients with Parkinson's disease (PD) who are undergoing microelectrode-guided internal globus pallidus (GPi) ablation. Images from thirty-seven adult patients with PD were reviewed and visualization of the GPi, globus pallidus externa (GPe), and the intervening lamina was noted. High-resolution images were acquired from all patients despite the external hardware and the patients' movement disorder. In all cases, the conventional surgical trajectory, determined indirectly by a fixed measurement from the anteroposterior commissure line, was modified by the ability to visualize the GPi and optic tract directly. This sequence facilitated accurate stereotactic targeting.

Adult↗

Neural information transferred from the putamen to the globus pallidus during learned movement in the monkey.

1. We studied the physiology of the neuronal projection from the striatum to the external and internal segments of the globus pallidus (GPe and GPi, respectively) in macaque monkeys. The objective of the study was to answer the following specific questions. 1) Which classes of the electrophysiologically identified striate neurons project to GPe and GPi? 2) What kind of information is transferred from the striatum to GPe and GPi during learned movement? 3) What are the physiological actions of striate projection neurons on target neurons in GPe and GPi? 4) What is the spatial pattern of the striatopallidal projections? 2. Sequential arm and orofacial movements were used as behavioral tasks. Visual stimuli triggered a sequence of three flexions-extensions of the elbow joint across the target, and the click of a solenoid valve triggered repetitive licking movements. 3. Striatopallidal projection neurons were electrophysiologically identified by antidromic activation after focal stimulation of either GPe or GPi. Of two classes of striate neurons, tonically active neurons (TANs) with tonic spontaneous discharges (2-8 imp/s) and broad action potentials, and phasically active neurons (PANs) with a very low spontaneous discharge rate (< 0.5 imp/ s) and high-frequency discharges in relation to behavioral tasks, PANs were identified as the projection neurons to either GPe or GPi. In 325 TANs examined by stimulation of GPe or GPi, no neuron was activated antidromically, even in the case of TANs located in the close vicinity of PANs that were identified as striatopallidal projection neurons. 4. The physiologically identified projection neurons (52 cells) in the striatum exhibited either discharges related to movement (30 cells) or discharges related to preparation for movement (4 cells) during performance of learned motor tasks. The activities of the remaining 17 striatopallidal neurons either were not related to the behavioral tasks used or could not be characterized sufficiently in the tasks. However, all of the unidentified striatopallidal neurons were PANs, on the basis of the spontaneous discharge rate and the shape of the action potential. 5. PANs with movement-related activity and those with preparation for movement-related activity were antidromically activated from the globus pallidus (GP). Not only the PANs that show burst discharges specifically at the beginning of a sequence of movement but also PANs that show phasic discharges time-locked to each movement of a sequence were identified as putaminopallidal projection neurons. On the other hand, no neurons that showed responses to sensory stimulus were identified as putaminopallidal neurons. 6. The conduction velocities of the putaminopallidal axons were estimated at approximately 1 m/s on the basis of the latency of antidromic activation and conduction distance. The PANs with activity only at the beginning of a sequential movement were more frequently found to project to GPi than to GPe, whereas the PANs with burst activity at each movement were more frequently found to project to GPe than to GPi. Among the GPi-projecting PANs, neurons with initial activity only showed a tendency to have longer latencies of activation from GPi than neurons with activity time-locked to each movement. 7. The physiological action of the striatopallidal projection was examined by switching from recording to microstimulation after identification of striatopallidal projection neurons in the putamen while recording evoked field potentials or spike discharges of single GP neurons located where the electrical stimulation evoked antidromic activation of the striate neurons with the lowest threshold. A small majority of GP neurons that exhibited increase of discharges during motor tasks received facilitatory putaminopallidal influences, whereas the vast majority of GP neurons that exhibited decrease of discharges during motor tasks received suppressive putaminopallidal influences.

Animals↗

The role of the GABA mechanisms of the globus pallidus in mediating catalepsy, stereotypy and locomotor activity.

Muscimol, picrotoxin and bicuculline were injected bilaterally through permanently implanted cannulae into either anterior (GPa) or posterior parts of the globus pallidus (GPp) of rats. Both the muscimol injected into the GPa and the picrotoxin injected into the GPp abolished or strongly inhibited spiperone (0.2 mg/kg, IP)-induced catalepsy. Muscimol alone (25-200 ng/0.2 microliter/GP) injected into the GPa evoked a dose-dependent biphasic effect: at first catalepsy (throughout 7.3 min), and then a long-lasting (more than 2 hr) locomotor stimulation and stereotyped sniffing. Muscimol (200 ng/GP) injected into GPp inhibited both the spontaneous motility and amphetamine-induced hyperactivity. Picrotoxin (200 and 400 ng/GP) injections into GPa and GPp produced an increase of the locomotor activity as well as stereotyped sniffing. Picrotoxin started to block muscimol hyperactivity when its own stimulatory action disappeared, thus also for picrotoxin the second phase of action could be detected. The globus pallidus is shown to be a relay station of impulses mediating neuroleptic catalepsy. Furthermore, it is suggested that behavioural changes induced by muscimol resulted from the action of the drug on at least 2 different neuronal systems, both being controlled by GABA receptors. One of them seems to be responsible for inducing neuroleptic-like catalepsy, and the other one for the hyperactivity and blockade of spiperone-catalepsy.

Animals↗

L-DOPA inhibits depolarization-induced [3H]GABA release in the dopamine-denervated globus pallidus of the rat: the effect is dopamine independent and mediated by D2-like receptors.

The effect of L-DOPA on [(3)H]GABA release in slices of globus pallidus from 6-OHDA-lesioned rats was studied. Release was evoked by high (15 mM) K(+). The lesion reduced dopamine content and dopamine synthesized from L-DOPA. The inhibition of DOPA decarboxylase blocked dopamine synthesis. Endogenous dopamine released by high K(+) inhibited [(3)H]GABA release in normal but not in lesioned slices. L-DOPA inhibited (IC(50) = 0.44 microM) evoked [(3)H]GABA release. The inhibition was via D2-like receptors but not mediated by dopamine. The turning behavior induced by L-DOPA methyl ester (25 mg/kg, i.p.) was not abolished by the DOPA decarboxylase inhibitor 3-hydroxybenzylhydrazine but in this condition it was abolished by sulpiride. Results suggest that L-DOPA acting as D2-like agonist inhibits GABA release in the rat globus pallidus and induces turning behavior in rats with unilateral lesions of the dopamine innervation. L-DOPA could control Parkinson's disease symptoms acting not only as dopamine precursor but also by itself.

Animals↗

Treatment of dystonic syndromes by chronic electrical stimulation of the internal globus pallidus.

AIM: Dystonia is a medically intractable condition causing twisting or myoclonic movements and abnormal postures. There is an important heterogeneity among etiologies of dystonia. The electrical stimulation of the globus pallidus has been used successfully in primary generalized dystonia. The aim of this study was to examine the long-term efficacy and safety of deep brain stimulation (DBS) in the treatment of primary and secondary generalized dystonia in children and adults. METHODS: Fifty-three patients were included. Electrodes were bilaterally implanted under stereotactic guidance and connected to neurostimulators, subcutaneously inserted. Efficacy was evaluated by comparing scores on the clinical and functional Burke-Marsden-Fahn dystonia rating scales (BMFDRS) before and after implantation. Patients were divided into 3 groups: group 1 comprised 15 patients with DYT1 dystonia; group 2, 17 patients with dystonia of unknown etiology and group 3, 21 patients with secondary dystonia. The mean follow-up was 26.6+/-12.3 months for primary dystonia and 23.1+/-11.8 for secondary dystonia. RESULTS: After 1 year, the improvement of the clinical score is 71% in group 1, 74% in group 2 and 31% in group 3. The functional score was improved by 63% in group 1, 49% in group 2 and 7% in group 3. We did not find any significant difference between children and adults. In secondary dystonia, efficacy of the stimulation is more limited. The efficacy of the stimulation improved with time for the 3 groups. COMCLUSION: Electrical stimulation of the internal globus pallidus proved to be an effective treatment for generalized dystonia and should be considered as first-line therapy.

Adult↗

Single subthalamic nucleus neurons project to both the globus pallidus and substantia nigra in rat.

The organization of the major efferents of the rat subthalamic nucleus (STN) was investigated using a fluorescent retrograde double-labeling technique. Red fluorescent Evans Blue was injected into the globus pallidus and blue fluorescent DAPI-Primuline was injected into the substantia nigra. After retrograde axonal transport many double-labeled neurons were seen throughout the STN. Occasionaly double-labeled cells were seen in the lateral hypothalamus just medial to the STN and in a thin lateral strip of neurons extending laterally from the STN. Evidence for a mediolateral topography in both the STN-pallidal and STN-nigral pathways was obtained. The STN contains few, if any, local interneurons. Cell counts revealed that at least 94% of, and possibly all, STN neurons send axon collaterals to both the globus pallidus and substantia nigra.

Animals↗

Effects of increasing doses of apomorphine during stereotaxic neurosurgery in Parkinson's disease: clinical score and internal globus pallidus activity. Short communication.

We analysed the firing activity of internal globus pallidus cells in two Parkinson's disease patients undergoing stereotaxic surgery. Both patients showed an advanced rigid-akinetic syndrome with disabling levodopa induced dyskinesias. Apomorphine, intraoperatively administered at doses (1-2 mg) inducing a short but clear clinical improvement without involuntary movements, reduced the pallidal discharge rate by > 50% in both patients. An higher apomorphine dose (2.5 mg), tested in one hemisphere, blocked the firing activity with a time course independent from the occurrence of dyskinesias. These finding suggest that the reduction of internal pallidus excitability is one of the mechanisms underlying the efficacy of dopaminergic therapy, but also that changes in other basal ganglia stations are likely to be involved in dyskinesias.

Antiparkinson Agents↗

Methods for programming and patient management with deep brain stimulation of the globus pallidus for the treatment of advanced Parkinson's disease and dystonia.

Globus pallidus (GPi) deep brain stimulation can markedly improve severe medication-refractory Parkinson's disease (PD) and dystonia. Appropriate perioperative patient management can assist with electrode implantation. Optimizing stimulation settings and simultaneously adjusting medications (when appropriate) can substantially improve patient outcomes. Although there are a large number of possible stimulation settings, in clinical practice, a relatively narrow range of settings has been shown to be most efficacious. A systematic approach to determining those settings that maximally improve parkinsonism and suppress drug-induced dyskinesias is outlined following a clear algorithm that uses the observation that stimulation of the dorsal and ventral pallidum has been shown to have opposite motor effects in PD. Based on the available literature, recommendations are also made for the use of GPi deep brain stimulation in dystonia.

Dystonia↗

Behavioral and biochemical assessment of time-related changes in globus pallidus and striatal dopamine induced by intranigrally administered neurotensin.

Microinjection of neurotensin (NT; 2 and 5 micrograms) into the substantia nigra zona compacta caused an increase in dopamine (DA) and DA metabolites in the rodent globus pallidus and striatum which persisted for at least 20 hours after peptide administration. Similar NT treatments given unilaterally into the nigra caused circling away from the injected side in amphetamine-pretreated rats, but were without effect when microinjected into saline-pretreated animals. Circling also occurred when the animals were given amphetamine 20 hours after intranigral NT administration. Contralateral rotation was observed with unilateral intranigral injections of gamma-hydroxybutyric acid (GHB; 400 micrograms) or with lower intranigral GHB doses (250 micrograms) in amphetamine-pretreated animals. The effects of GHB and NT differed in the manner in which the animals rotated as well as in the profile of DA and DA metabolite changes induced by these drugs. These studies indicated that: dopaminergic functions of the globus pallidus are influenced, like the striatum, by manipulations of the substantia nigra: NT and GHB likely act via different mechanisms to effect nigral dopamine-containing cells; and NT was capable of inducing changes in dopamine neurons which had long term consequences.

Animals↗