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Results for “Subthalamic Nucleus”

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PubMed2000

Increased behavioral response to dopaminergic stimulation of the subthalamic nucleus after nigrostriatal lesions.

Local infusions of the nonselective dopaminergic agonist apomorphine into the subthalamic nucleus of rats has been shown to elicit orofacial dyskinesia which can be blocked by D1 but not D2 receptor antagonists. In the present study, we show that the selective D1 agonist A77636 also induces orofacial dyskinesia when injected into the subthalamic nucleus of awake rats, thus confirming a role for D1 receptors in this effect. We also examined the dyskinesia induced by intrasubthalamic injections of apomorphine in rats with an ipsilateral lesion of the nigrostriatal pathway. The orofacial response to local administration of apomorphine (1.0 microg) into the subthalamic nucleus was markedly increased in the lesioned rats. As in control rats, the enhanced behavioral response seen in lesioned rats was blocked by peripheral administration of D1 antagonists. Although D1 receptor binding autoradiography revealed no difference in D1 receptor binding in the subthalamic nucleus on the side of the lesion compared to controls, D1 binding was higher in the subthalamic nucleus on the side of the lesion compared to the contralateral side. The increased behavioral response observed after unilateral dopamine denervation suggests that the subthalamic nucleus is tonically regulated by dopaminergic projections from the substantia nigra. Furthermore, the data suggest that subthalamic D1 receptors may be involved in the development of dyskinesia induced by dopaminergic drugs.

Adamantane↗

PubMed2006

Induction of immediate early gene expression by high-frequency stimulation of the subthalamic nucleus in rats.

Deep brain stimulation is associated with delayed improvement of parkinsonian symptoms, such as hypokinesia with subthalamic nucleus stimulation, or dystonia with globus pallidus internus stimulation. The latency observed is better explained by molecular alterations than immediate electrophysiological processes, and clinical improvement may involve adaptive gene expression. Here, we have studied immediate early gene expression as fast molecular response to subthalamic nucleus stimulation. Bipolar electrodes were implanted bilaterally into the subthalamic nucleus of anesthetized male Wistar rats. High-frequency stimulation (130 Hz or 80 Hz, 60 micros, 300 microA) or low-frequency stimulation (5 Hz, 60 micros, 300 microA) was performed with the right electrode for 15, 60, 120, and 240 min whereas the silent left electrode served as negative control. Brains were fixed by transcardial perfusion and frozen sections were stained with polyclonal antibodies directed against three immediate early gene-encoded proteins, c-Fos, c-Jun, and Krox-24 (NGFI-A, Egr-1, Zif268, Tis8, Zenk). After 120 and 240 h, c-Fos immunoreactivity was strongly upregulated in subthalamic nucleus neurons on the stimulated site. In contrast, no c-Fos immunoreactivity was detected on the non-stimulated site except for single positive cells located in close proximity to the electrode tracks. Furthermore, c-Fos immunoreactivity was induced in subthalamic nucleus projection areas, such as primary and secondary motor cortex, primary somatosensory and insular cortex, lateral and medial globus pallidus, suprageniculate thalamic nucleus, pontine nuclei, medial geniculate nucleus, and substantia nigra. Similarly, c-Jun and Krox-24 were induced at the site of stimulation and in projection areas following high-frequency subthalamic nucleus stimulation. Whereas high frequency stimulation with 80 Hz was similarly effective none of the three immediate early gene-encoded proteins was induced with low-frequency stimulation (5 Hz) for 4 h. This is in accordance with the therapeutic effects of deep brain stimulation which are only elicited with high frequency stimulation. Our data provide evidence that immediate early gene expression in the subthalamic nucleus is rapidly and substantially induced by high-frequency stimulation. The induction of immediate early genes in projection sites suggests ipsilateral transsynaptic modulation of neuronal activity.

Animals↗

PubMed2004

Ablation of the subthalamic nucleus protects dopaminergic phenotype but not cell survival in a rat model of Parkinson's disease.

Inhibition or ablation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD) does not only reverse motor deficits, silencing the glutamatergic output of the subthalamic nucleus, but has also been implicated to have neuroprotective effects on nigral neurons in animal models of Parkinson's disease. Ablation of the subthalamic nucleus has been shown to increase the number of tyrosinhydroxylase-immunopositive cells and partially restores behavioral deficits in animal models of Parkinson's disease. However, it is unclear whether subthalamic nucleus ablation indeed prevents cell death or whether the effect is due to the rescue of the dopaminergic (DA) phenotype of impaired cells by upregulating tyrosine hydroxylase (TH). We therefore investigated the potential neuroprotective effects of a preceding subthalamic nucleus lesion on 6-hydroxydopamine (6-OHDA)-induced nigral cell death and compared the retrograde tracer fluorogold (FG) as a marker of cell survival with tyrosinhydroxylase immunoreactivity as a marker of the dopaminergic phenotype. In the present study, we show that ablation of the subthalamic nucleus does not affect the number of fluorogold-labeled cells but increases the number of tyrosinhydroxylase-positive neurons in subthalamic nucleus-lesioned hemiparkinsonian animals and leads to partial behavioral recovery of the rats. We conclude that subthalamic nucleus ablation exerts neuroprotective properties on the dopaminergic nigrostriatal pathway against 6-hydroxydopamine toxicity in terms of rescuing the neurotransmitter phenotype in the remaining neurons rather than enhancing the total number of nigral cells.

Animals↗

PubMed2003

Effects of subthalamic nucleus stimulation on urodynamic findings in patients with Parkinson's disease.

PURPOSE: Although the effects of subthalamic nucleus stimulation on the control of motor symptoms in patients with Parkinson's disease have been demonstrated, to our knowledge there are no data on effects of this treatment on voiding. We evaluated differences in urodynamic findings in patients with Parkinson's disease during on and off subthalamic nucleus stimulation status. MATERIALS AND METHODS: We evaluated 3 males and 2 females with Parkinson's disease. All patients had undergone surgical bilateral implantation of subthalamic nucleus electrodes 4 to 9 months before our observation. Urodynamic evaluation was performed during chronic subthalamic nucleus stimulation and 30 minutes after turning off the stimulators. Certain parameters were evaluated, including bladder compliance and capacity, first desire to void volume, bladder volume of appearance (reflex volume) and amplitude of detrusor hyperreflexic contractions, maximum flow, detrusor pressure at maximum flow and detrusor-sphincter coordination. Results were compared statistically. RESULTS: Statistically significant differences in urodynamic data obtained during on and off subthalamic nucleus stimulation status were noted. In particular bladder capacity and reflex volume were increased for on status (median 320 versus 130 ml., p = 0.043 and 250 versus 110, p = 0.043, respectively). The amplitude of detrusor hyperreflexic contractions was decreased for on status but the difference was not significant (median 23 versus 37 cm. H2O, p = 0.223). No differences were noted in the other urodynamic parameters considered during the filling and voiding phases. CONCLUSIONS: Our experience shows that subthalamic nucleus stimulation seems to be effective for decreasing detrusor hyperreflexia in Parkinson's disease cases. This finding confirms a role for basal ganglia in voiding control.

Aged↗

PubMed1996

The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the output of the basal ganglia in the monkey.

The aim of the present study was to elucidate the organization of the interconnections between the subthalamic nucleus and the two segments of the globus pallidus in squirrel monkeys. By making small deposits of tracers in the two segments of the globus pallidus, we demonstrate that interconnected neurons of the subthalamic nucleus and the external pallidum innervate, via axon collaterals, the same population of neurons in the internal pallidum. Furthermore, this organizational principle holds true for different functional regions of the pallidum and the subthalamic nucleus. Injections of biotinylated dextran amine were made in the dorsal (associative), ventrolateral (sensorimotor) and rostromedial (limbic) regions of the internal pallidum. Following these injections, there were rich clusters of labelled terminals in register with retrogradely labelled perikarya in related functional regions of the subthalamic nucleus and the external pallidum. At the electron microscopic level, the majority of labelled terminals in the external pallidum displayed the ultrastructural features of boutons from the subthalamic nucleus and were non-immunoreactive for GABA, whereas those in the subthalamic nucleus resembled terminals from the external pallidum and displayed GABA immunoreactivity. In both cases, the synaptic targets of the labelled terminals included labelled neurons. These observations suggest that the biotinylated dextran amine injected in the internal globus pallidus was transported retrogradely to perikarya in the external pallidum and the subthalamic nucleus and then anterogradely, via axon collaterals, to the subthalamic nucleus and the external pallidum respectively. This suggestion was supported by injections of biotinylated dextran amine or Phaseolus vulgaris-leucoagglutinin in regions of the external pallidum that corresponded to those containing retrogradely labelled cells following injections in the internal pallidum. The clusters of labelled cells and varicosities that resulted from these injections were found in regions of the subthalamic nucleus similar to those labelled following injections in the internal globus pallidus. Furthermore, terminals from the external pallidum and the subthalamic nucleus converged on the same regions in the internal globus pallidus. The results of the present tracing study define the basic network underlying the interconnections between the external segment of the globus pallidus and the subthalamic nucleus, and their connections with the output neurons of the basal ganglia in primates.

Animals↗

PubMed1996

Activity of neurons of the subthalamic nucleus in relation to motor performance in the cat.

The activity of subthalamic nucleus neurons related to motor performance was studied in three unrestrained cats operantly conditioned to perform a lever-release movement. The movement was initiated either rapidly after the trigger stimulus (a brief sound) in a simple reaction-time paradigm or after a delay in trials identified by a tone cue. These paradigms were randomly presented. The activity of 171 neurons was recorded in the contralateral and in the ipsilateral subthalamic nucleus, with respect to the performing limb. The mean spontaneous activity of cells in the ipsilateral side (18.5 +/- 13.8 imp/s, mean +/- SD) was higher than that in the contralateral side (8.5 +/- 8.1 imp/s). A total of 145 cells (85%) presented significant changes in activity in relation to the lever-release movement (task-related cells). The remaining 26 cells were either related to other events of the task (n = 15; lever-press or reinforcement occurrence) or not related at all to the task performance (n = 11). The majority of changes of activity of task-related cells were initial increases in discharge, which started on average, 127 ms before movement onset and lasted several hundreds of milliseconds. These increases in discharge were more frequent in the contralateral side (75 of 80 task-related cells, 94%) than in the ipsilateral side (43 of 65 task-related cells, 66%). The changes in activity, either increases or decreases, occurred early after the trigger stimulus, since 62% of them had a latency of less than 100 ms. Although the mean latency of initial increases was rather similar in both sides (97 ms contralateral versus 104 ms ipsilateral), the contralateral side was characterized by a high proportion of very early responses (less than 20 ms). For most neurons, the early changes in activity described above were absent after the trigger stimulus in the delayed condition. For certain neurons, the changes in activity prior to movement were different in reaction-time condition and in delayed condition, showing that the pattern of activity preceding movement might depend on the temporal requirements for motor initiation. The results suggest that a significant proportion of subthalamic cells are involved in the preparation and the initiation phases of the lever-release movement studied, although other hypotheses (e.g. stimulus-related responses) cannot be definitely ruled out. The timings and patterns of the changes in activity observed in the subthalamic nucleus in the present study, and in the pallidal complex previously, cannot be explained easily by the classical scheme where the external pallidum inhibits the subthalamic nucleus. The results suggest rather that the subthalamic nucleus, driven by a yet-to-be-determined excitatory input, exerts an excitatory influence on the pallidum and plays a crucial role in the control of the basal ganglia output neurons.

Acoustic Stimulation↗

PubMed1982

Electron microscopy of the subthalamic nucleus in the baboon. II. Experimental demonstration of pallido-subthalamic synapses.

The present study demonstrates the existence in the baboon of a powerful ipsilateral pallido-subthalamic projection, composed of myelinated fibers. These axons give rise to type I (F) terminals, including all subtypes identified by Hassler et al. (1982), and terminate on the perikarya of the subthalamic relay neurons, on proximal dendrites, and on somatic and dendritic spines. Endings on subthalamic interneurons could not be found. Following experimental lesions in the pallidum externum, these pallido-subthalamic neurons undergo distinctive changes characterized as "pale", "intermediate" and "dark" degeneration, the form of the degeneration depending on the survival times of 3, 4 and 5 days. The ratios between the individual types of degeneration may vary. The ultrastructural features of the pallido-subthalamic terminals, which are believed to be GABA-ergic (Fonnum et al., 1978), are different from those of the GABA-ergic striato-nigral connections (Kim et al., 1971). After pallidum externum lesions, the pale form of degeneration is found in a few instances in the contralateral subthalamic nucleus in the type IX mini-synapses and the type I (F) beak-shaped synapses. There is a considerable convergence of different afferents with specialized synapses on the somata, stem dendrites, and dendritic spines of the neurons of the subthalamic nucleus.

Animals↗

PubMed2002

Dopamine D1/5 receptor stimulation induces c-fos expression in the subthalamic nucleus: possible involvement of local D5 receptors.

The activity of neurons in the subthalamic nucleus controls various aspects of movement. The present study examined the action of dopamine receptor agonists on c-fos gene expression in the subthalamic nucleus in normal rats. We found that systemic administration of the dopamine D1/5 receptor agonist, SKF 82958 (1 mg/kg), induces c-fos expression in the subthalamic nucleus. In contrast, systemic administration of the dopamine D2/3 receptor agonist, quinelorane (2 mg/kg) had no effect. When combined, SKF 82958 and quinelorane induced c-fos expression in subthalamic neurons that was similar to that found following administration of SKF 82958 alone. We also examined c-fos expression in the substantia nigra pars reticulata, the major projection area for subthalamic neurons, and found that SKF 82958, but not quinelorane, caused an induction of c-fos expression in this area. In order to clarify the mechanisms underlying the SKF 82958-mediated induction of c-fos expression in the subthalamic nucleus and substantia nigra pars reticulata, in situ hybridization for the dopamine D1, D2, D3 and D5 receptor mRNAs was performed. The only significant observation was that D5 receptor mRNA is expressed in subthalamic neurons. The present data show that dopamine, via D1/D5 receptors, upregulates c-fos expression in subthalamic neurons, and that the high expression of D5 receptors in this area might be involved. Taken together, these data suggest that dopamine D1/5 receptors are more important for the action of dopamine in the so-called indirect pathway of the basal ganglia circuitry than what is recognized in current models of basal ganglia organization.

Animals↗

PubMed2003

Surgery of the subthalamic nucleus: use of movement-related neuronal activity for surgical navigation.

THE BASAL GANGLIA have important roles in somatic motor, oculomotor, limbic, and associative functions. These functions are represented in anatomically distinct territories in each basal ganglion nucleus. During surgery of the subthalamic nucleus for Parkinson's disease, the primary goal is to influence the physiology of the motor territory without affecting nonmotor areas. This article describes the use of movement-related cellular activity during single-unit microelectrode mapping to identify and to navigate within the motor territory of the subthalamic nucleus.

Brain Mapping↗

PubMed2004

Is the subthalamic nucleus hypointense on T2-weighted images? A correlation study using MR imaging and stereotactic atlas data.

BACKGROUND AND PURPOSE: Although the subthalamic nucleus is the most frequently used target for surgical treatment of Parkinson's disease, the criteria on which it can be identified on T2-weighted images have never been clearly defined. This study was conducted to characterize the precise anatomic distribution of T2-weighted hyposignal in the subthalamic region and to correlate this hyposignal with iron content in the subthalamic nucleus. METHODS: The T2-weighted MR imaging acquisitions of 15 patients with Parkinson's disease were fused with a digitized version of the Schaltenbrand and Wahren anatomic atlas. The MR signal intensity within the anatomic limits of the subthalamic nucleus was evaluated. An anatomic specimen obtained at autopsy was used to evaluate iron content. RESULTS: In all patients, the subthalamic nucleus was hypointense on both sides in the anterior half of the nucleus. At more posterior levels of the nucleus, hypointensity was less frequently observed (20-80%). Hypointensity was never observed at the most posterior pole. Iron was present in the anteromedial part of the nucleus but absent at the most posterior levels. CONCLUSION: The hypointense signal intensity located lateral to the red nucleus and dorsolateral to the substantia nigra correlates with the presence of iron and corresponds anatomically to the subthalamic nucleus. It can therefore be used as a landmark for electrode implantation in patients with Parkinson's disease. It should, however, be emphasized that although hypointensity was always present in the anterior half of the subthalamic nucleus, the posterior part of the nucleus was not visible in most cases.

Adult↗

PubMed2005

Bilateral subthalamic nucleus stimulation for Parkinson's disease: a systematic review of the clinical literature.

OBJECTIVE: To evaluate the benefits and adverse effects of bilateral subthalamic nucleus stimulation in the treatment of Parkinson's disease (PD) by systematically reviewing the published literature. METHODS: A search of the PubMed database using the key words subthalamic, nucleus, and stimulation yielded 624 articles published between 1966 and December 2003. Only articles that included original, nonduplicated descriptions of patients with PD treated with bilateral subthalamic nucleus stimulation were selected for further analysis. RESULTS: A total of 38 studies from 34 neurosurgical centers in 13 countries were identified for critical review. The outcomes for 471 patients with PD treated with bilateral subthalamic nucleus stimulation were assessed according to the Unified Parkinson's Disease Rating Scale in both on-medication and off-medication conditions. With stimulation, Unified Parkinson's Disease Rating Scale motor scores in the off-medication condition improved by 50% after 6 months, 56% after 12 months, 51% after 2 years, and 49% after 5 years compared with preoperative off-medication scores. At 12 months of subthalamic nucleus stimulation, the mean improvement in tremor was 81%, in rigidity was 63%, in bradykinesia was 52%, in gait was 64%, and in postural instability was 69% when compared with preoperative off-medication subscores. On-medication dyskinesias were reduced by 94%, as assessed 12 months after stimulation using the Unified Parkinson's Disease Rating Scale IV complications of therapy score. There was an overall 52% reduction in the l-dopa-equivalent dose intake after 12 months of stimulation. Most adverse effects were mild to moderate. There was a 1 to 2% incidence of severe adverse effects (death or permanent neurological deficits related to intracerebral hemorrhages). Nineteen percent of the patients had adverse effects related to stimulation that could be reversed by changing stimulation parameters. There was a 9% incidence of adverse effects related to the hardware (infections, lead and pulse generator problems). CONCLUSION: Bilateral subthalamic nucleus stimulation is effective in the treatment of PD. Further refinements in patient selection and surgical technique may lessen the incidence of complications associated with this procedure.

Electric Stimulation Therapy↗

PubMed1982

Perikaryal cell labeling in the subthalamic nucleus following the injection of 3H-gamma-aminobutyric acid into the pallidal complex: an autoradiographic study in cat.

Although the subthalamic nucleus is thought to exert a major influence on the corpus striatum output cells, there is little information available on the transmitter or transmitters involved. In a series of autoradiographic experiments in which various different radiolabeled putative transmitter substances were injected separately into the pallidal complex of cats, it was noted that 3H-gamma-aminobutyric acid injection consistently resulted in perikaryal labeling in the subthalamic nucleus. 3H-gamma-aminobutyric acid injection in the lateral part of the external pallidal segment resulted in labeled cells situated laterally in the subthalamic nucleus, while 3H-aminobutyric acid injection in the internal pallidal segment (entopeduncular nucleus) resulted in cell labeling more medially in the subthalamic nucleus. Perikaryal cell labeling was also noted in the lateral putamen following 3H-gamma-aminobutyric acid injection in the external pallidal segment in cats pretreated with systemic amino-oxyacetic acid. No cell groups other than the striatum and subthalamic nucleus could be made to label with 3H-gamma-aminobutyric acid. Furthermore, no perikaryal cell labeling in the subthalamic nucleus was seen to follow injections of 3H-D-aspartate or 3H-serotonin into the pallidal complex. The findings suggest that 3H-gamma-aminobutyric acid, but not aspartate or serotonin, undergoes high affinity uptake and retrograde transport by subthalamo-pallidal neurons. Bearing in mind the many reservations discussed, the observation implies that 3H-gamma-aminobutyric acid may be a transmitter in the subthalamo-pallidal pathway.

Animals↗

PubMed2002

Superior colliculus firing changes after lesion or electrical stimulation of the subthalamic nucleus in the rat.

Recent data have suggested a critical role for the basal ganglia in the remote control of epileptic seizures. In particular, it has been shown that inhibition of either substantia nigra pars reticulata or subthalamic nucleus as well as activation of the superior colliculus suppresses generalized seizures in several animal models. It was previously shown that high frequency stimulation of the subthalamic nucleus, thought to act as functional inhibition, stopped ongoing non-convulsive generalized seizures in rats. In order to determine whether high frequency stimulation of the subthalamic nucleus involved an activation of superior colliculus neurons, we examined the effects of subthalamic nucleus manipulation, by either high frequency stimulation or chemical lesion, on the spontaneous electrical activity of superior colliculus neurons. Acute high frequency stimulation of the subthalamic nucleus (frequency 130 Hz) induced an immediate increase of unitary activity in 70% of responding cells, mainly located within the deep layers, whereas a reduction was observed in the remaining 30%. The latter responses are dependent on the intensity and frequency of the stimulation. Unilateral excitotoxic lesion of the subthalamic nucleus induced a delayed and transient decrease of superior colliculus activity. Our data suggest that high frequency stimulation of the subthalamic nucleus suppresses generalised epileptic seizures through superior colliculus activation.

Action Potentials↗

PubMed2006

Experience with microelectrode guided subthalamic nucleus deep brain stimulation.

OBJECTIVE: Subthalamic deep brain stimulation (DBS) has rapidly become the standard surgical therapy for medically refractory Parkinson disease. However, in spite of its wide acceptance, there is considerable variability in the technical approach. This study details our technique and experience in performing microelectrode recording (MER) guided subthalamic nucleus (STN) DBS in the treatment of Parkinson disease. METHODS: Forty patients underwent surgery for the implantation of 70 STN DBS electrodes. Stereotactic localization was performed using a combination of magnetic resonance and computed tomographic imaging. We used an array of three microelectrodes, separated by 2 mm, for physiological localization of the STN. The final location was selected based on MER and macrostimulation through the DBS electrode. RESULTS: The trajectory selected for the DBS electrode had an average pass through the STN of 5.6 +/- 0.4 mm on the left and 5.7 +/- 0.4 mm on the right. The predicted location was used in 42% of the cases but was modified by MER in the remaining 58%. Patients were typically discharged on the second postoperative day. Eighty-five percent of patients were sent home, 13% required short-term rehabilitation, and one patient required long-term nursing services. Seven complications occurred over 4 years. Four patients suffered small hemorrhages, one patient experienced a lead migration, one developed an infection of the pulse generator, and one patient suffered from a superficial cranial infection. CONCLUSION: Simultaneous bilateral MER-guided subthalamic DBS is a relatively safe and well-tolerated procedure. MER plays an important role in optimal localization of the DBS electrodes.

Aged↗

PubMed2001

Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus, which is reversed by the lesion of the subthalamic nucleus in the rat.

The role of the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinson's disease is still unclear. Using microrecordings, we investigated the changes occurring in PPN neurons after lesions of the substantia nigra compacta (SNc) and the role of the subthalamic nucleus (STN) in these changes. In normal rats the firing rate of PPN neurons was 10.6 +/- 1.4 spikes/s, the majority of neurons (91%) having a regular firing pattern, 6% irregular and 3% in bursts. In rats with 6-hydroxydopamine lesions of the SNc, the firing rate increased significantly to 18.3 +/- 3.0 spikes/s compared with normal rats. In addition, the firing pattern changed significantly: 70% of the neurons discharged regularly, 27% irregularly and 3% in bursts. In rats with ibotenic acid lesions of the STN, the firing rate decreased significantly to 7.2 +/- 0.9 spikes/s and the firing pattern changed significantly: 50% of the neurons discharged regularly, 43% irregularly and 7% in bursts. The rats with combined SNc and STN lesions showed no change in the firing rate (8.5 +/- 1.0 spikes/s) compared to normal rats. The firing pattern changed significantly: 69% of the cells discharged regularly, 26% irregularly and 5% in bursts. These findings demonstrate that PPN neurons are overactive and more irregular in the 6-hydroxydopamine-lesioned rats, suggesting the implication of this nucleus in the pathophysiology of parkinsonism. Moreover, the fact that STN lesions induced a reduction in the firing rate of the PPN in normal rats and a normalization of the firing rate in rats with 6-hydroxydopamine lesions suggests that this nucleus is under major control of the STN.

Action Potentials↗

PubMed1992

Differential effect of subthalamic nucleus ablation on dopamine D1 and D2 agonist-induced rotation in 6-hydroxydopamine-lesioned rats.

The effect of unilateral subthalamic nucleus ablation on rotation in response to dopamine D1 and D2 agonists was examined in rats with a unilateral 6-OHDA lesion of the nigrostriatal pathway. Four to five weeks following subthalamic nucleus lesion, D2 agonist-induced rotation was reduced in subthalamic nucleus-lesioned rats relative to sham controls, although no such reduction in D1 agonist-induced circling occurred. However, 1-2 weeks following subthalamic nucleus lesion marked reductions occurred in both D1 and D2 agonist-induced rotation in subthalamic nucleus lesioned rats compared to sham controls. These results suggest that the subthalamic nucleus contributes primarily to the expression of D2-mediated motor behaviors, although ablation of the subthalamic nucleus may induce certain time-dependent compensatory mechanisms in other basal ganglia structures which affect D1-mediated actions.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2002

Enhanced food-related motivation after bilateral lesions of the subthalamic nucleus.

Although inactivation of the subthalamic nucleus (STN) has beneficial effects on motor symptoms of parkinsonism, little is known of possible actions on nonmotor symptoms of cognition or mood. Here, we used several forms of converging evidence to show that STN lesions can enhance behavioral motivation. Thus, bilateral fiber-sparing lesions of the STN in rats reduced the time required to eat a standard number of food reward pellets, without affecting food intake, and altered performance on a number of behavioral measures consistent with enhanced motivation for food. Thus, STN-lesioned rats showed greater levels of locomotor activity conditioned to food presentation, enhanced control over responding by food-related conditioned reinforcers, and a higher breaking point associated with elevated rate of lever press under a progressive ratio schedule of reinforcement. These results reveal a new functional role schedule for STN, possibly because of its involvement in ventral, as well as dorsal, striatal circuitry and are relevant to the therapeutic effects of STN stimulation in Parkinson's disease.

Analysis of Variance↗

PubMed2004

Synaptic release of dopamine in the subthalamic nucleus.

The direct modulation of subthalamic nucleus (STN) neurons by dopamine (DA) neurons of the substantia nigra (SN) is controversial owing to the thick caliber and low density of DA axons in the STN. The abnormal activity of the STN in Parkinson's disease (PD), which is central to the appearance of symptoms, is therefore thought to result from the loss of DA in the striatum. We carried out three experiments in rats to explore the function of DA in the STN: (i) light and electron microscopic analysis of tyrosine hydroxylase (TH)-, dopamine beta-hydroxylase (DbetaH)- and DA-immunoreactive structures to determine whether DA axons form synapses; (ii) fast-scan cyclic voltammetry (FCV) to determine whether DA axons release DA; and (iii) patch clamp recording to determine whether DA, at a concentration similar to that detected by FCV, can modulate activity and synaptic transmission/integration. TH- and DA-immunoreactive axons mostly formed symmetric synapses. Because DbetaH-immunoreactive axons were rare and formed asymmetric synapses, they comprised the minority of TH-immunoreactive synapses. Voltammetry demonstrated that DA release was sufficient for the activation of receptors and abolished by blockade of voltage-dependent Na+ channels or removal of extracellular Ca2+. The lifetime and concentration of extracellular DA was increased by blockade of the DA transporter. Dopamine application depolarized STN neurons, increased their frequency of activity and reduced the impact of gamma-aminobutyric acid (GABA)-ergic inputs. These findings suggest that SN DA neurons directly modulate the activity of STN neurons and their loss may contribute to the abnormal activity of STN neurons in PD.

Animals↗