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(The FASEB Journal. 2005;19:1771-1777.)
© 2005 FASEB

Dopamine receptors set the pattern of activity generated in subthalamic neurons

J. Baufreton*,{dagger}, Z.-T. Zhu{ddagger}, M. Garret*, B. Bioulac*, S. W. Johnson{ddagger} and A. I. Taupignon*,1

* UMR 5543, University Victor Segalen, Bordeaux, France;
{dagger} Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; and
{ddagger} Departments of Physiology and Pharmacology, and Neurology, Oregon Health and Science University, Portland, Oregon, USA

1 Correspondence: University Victor Segalen, 146 rue Saignat, Bordeaux, 33076 cedx France. E-mail: anne.taupignon{at}umr5543.u-bordeaux2.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 DOPAMINE RECEPTORS CONTROL...
 FUNCTIONAL DOPAMINE RECEPTORS...
 D1 AND D2 RECEPTORS...
 DOPAMINE-DEPLETED STATE:...
 MATERIALS AND METHODS
 REFERENCES
 
Information processing in the brain requires adequate background neuronal activity. As Parkinson’s disease progresses, patients typically become akinetic; the death of dopaminergic neurons leads to a dopamine-depleted state, which disrupts information processing related to movement in a brain area called the basal ganglia. Using agonists of dopamine receptors in the D1 and D2 families on rat brain slices, we show that dopamine receptors in these two families govern the firing pattern of neurons in the subthalamic nucleus, a crucial part of the basal ganglia. We propose a conceptual frame, based on specific properties of dopamine receptors, to account for the dominance of different background firing patterns in normal and dopamine-depleted states.— Baufreton, J., Zhu, Z.-T., Garret. M., Bioulac, B., Johnson, S. W., Taupignon, A. I. Dopamine receptors set the pattern of activity generated in subthalamic neurons.


Key Words: subthalamic nucleus • slow-wave sleep • burst-firing • basal ganglia


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
DOPAMINE RECEPTORS CONTROL...
 FUNCTIONAL DOPAMINE RECEPTORS...
 D1 AND D2 RECEPTORS...
 DOPAMINE-DEPLETED STATE:...
 MATERIALS AND METHODS
 REFERENCES
 
NEURONS IN SEVERAL AREASthroughout the brain rhythmically fire action potentials. There are two stereotypic firing modes: regular, single spikes (known as "tonic" or "pacemaking" firing) and clusters of high-frequency spikes (called "burst" firing). These two firing modes may be sustained rhythms or appear singly. For example, in thalamocortical neurons, they are gated by modulatory inputs from the brain stem that convey information on the overall level of vigilance (1) . Sustained, large-scale, synchronized burst-firing is most commonly found in slow-wave sleep and, to a lesser extent, in somnolence and drowsiness, when little or no information is relayed by the thalamus. Tonic firing is mostly associated with vigilance and attention (2 3 4) . In addition, the two modes reflect different processing functions, where bursts appear as a unit of neural information (5 , 6) . Bursting relies on specific cell-intrinsic mechanisms gated by sensory feedback and other inputs that carry information on extrasensory variables (7 , 8) .

Pathological states involve inappropriate burst-firing (9). Work in the last decade established burst-firing in basal ganglia as a hallmark of Parkinson’s disease. Neurons in the component nuclei of patients and animal models of Parkinson’s disease often sustain bursting in the absence of movement.

Among the component nuclei, the subthalamic nucleus (STN) is in a pivotal position to influence movement. The STN is composed of glutamate-containing neurons that participate in the so-called "indirect" pathway of basal ganglia connections (10) . The STN receives inhibitory GABA input from the globus pallidus externa, and it receives excitatory glutamatergic inputs from cerebral cortex, the parafascicular nucleus of the thalamus, and the pedunculopontine nucleus (11) . In turn, the STN sends excitatory synaptic inputs to substantia nigra reticulata and globus pallidus interna, which are the main output nuclei of the basal ganglia (12) . The STN has long been implicated in movement disorders. For example, lesions to the STN are known to induce hyperkinetic movements such as chorea and hemibalismus (13) . Furthermore, deep brain stimulation of the STN has been found to alleviate symptoms of Parkinson’s disease (14 , 15) . In humans and in primate and rodent models of Parkinson’s disease at rest, the STN shows a significant proportion of neurons in sustained burst-firing mode whereas single spike discharge is more prevalent in the normal state (16 17 18 19 20 21) . The cause of the marked proclivity to burst-firing in the dopamine-depleted state is not known, nor why it is detrimental to movement. However, clinical improvement in Parkinsonian patients has recently been correlated to a shift from bursting activity to nonbursting discharge, further supporting the assertion that burst-firing in the STN plays a harmful role (22) .

In vitro, subthalamic neurons from normal animals display tonic firing: very few neurons spontaneously fire in bursts. All neurons express the same repertoire of calcium channels (23) , so the heterogeneity in firing modes arises from a difference in the efficiency of potassium channel activity (24) . A vast majority of neurons, however, switch from tonic to burst-firing mode under various conditions (25 26 27 28) , suggesting that steady burst-firing is due to intrinsic properties. Furthermore, most neurons are intrinsically burst-competent under normal conditions, as they show stimulation-evoked bursts ("plateau potentials") or post-inhibitory rebound bursts, triggered by synaptic inputs (29 , 30) or current injections (18 , 24 , 28 , 31 32 33 34) .

Our working hypothesis is that, in the normal state, the intrinsic properties underlying tonic firing are promoted while burst-firing is restricted to significant information processing and gated by relevant synaptic inputs. We further presume that dopamine depletion leads to expression of the intrinsic properties that enable burst-firing.


   DOPAMINE RECEPTORS CONTROL SUBTHALAMIC FIRING IN VITRO
TOP
 ABSTRACT
 INTRODUCTION
 DOPAMINE RECEPTORS CONTROL...
FUNCTIONAL DOPAMINE RECEPTORS...
 D1 AND D2 RECEPTORS...
 DOPAMINE-DEPLETED STATE:...
 MATERIALS AND METHODS
 REFERENCES
 
One key assumption of current models of the basal ganglia is that dopamine acts in the striatum, indirectly inhibiting STN firing activity by acting on D2 receptors (35) . However, dopaminergic fibers from the substantia nigra do innervate the STN in rodents, primates, and humans (36 37 38 39) . Dopamine acts via five receptor subtypes (D1-D5) in two receptor families: D2 (D3, D2, and D4 subtypes) and D1 (D1 and D5 subtypes). All are prototypic of G-protein-coupled receptors (40) . A body of experimental results indicates that functional dopamine receptors are expressed in the STN but there is no agreement on the receptor subtypes (20 , 21 , 41 42 43 44) .

For these reasons, we sought to shed light on receptors that are functionally active in the STN, using specific agonists in the two dopamine receptor families on brain slices. We previously showed that activating dopamine receptors strengthened electrical activity, both in single spike-generating neurons (45 , 46) and in the subset of neurons with burst-firing capacity (34) . This resulted in an increased tonic-firing frequency as well as longer discharges of spontaneous or evoked bursts via actions on receptors in the D2 and D1 families, respectively. We now present additional results and propose a conceptual frame to account for the dominance of tonic firing in the normal state and the emergence of burst-firing in the dopamine-depleted state.

We first examined the action of agonists of dopamine receptors in the D1 and D2 families on driven firing. Subthalamic neurons give specific responses to short current pulses at hyperpolarized level. These are correlated to their capacity to generate bursts (in addition to single spikes) or single spikes only (25 , 33 , 34) . Upon stimulation, burst-competent neurons produce plateau potentials with action potentials at high frequency. Plateau potentials always outlast stimuli and resemble evoked bursts. In contrast, burst-incompetent neurons produce volleys of mostly regularly spaced spikes with a duration determined by the stimuli. Activating receptors in the D1 family only increased the firing frequency of such neurons (Fig. 1 ). The mean firing rate in control was 39 ± 4 Hz and 53 ± 5 Hz in the presence of D1 agonists (n=6), while three other neurons displayed no change in firing rate. There was no other significant change. Coapplication of an antagonist of D1-like receptors, SCH 23390 (10 µM), reversed these changes, indicating that D1 receptors were specifically activated. In contrast, activating receptors in the D2 family in burst-competent neurons led to several changes. It significantly reduced all the indexes of burst efficacy in 10 of 13 burst-competent neurons. The evoked-burst duration and number of action potentials fired per evoked burst were reduced and membrane potential was depolarized (Fig. 2 ). Mean burst duration in control was 2.1 ± 0.6 s. This value was markedly lower in the presence of quinpirole (1.4±0.4 s; n=10). There was also a significant reduction in the number of action potentials fired per burst (98±23 in control vs. 61±16; n=10) in the same neuron sample. The mean membrane potential change was +2.9 ± 0.8 mV (n=10). Receptors in the D2 family were specifically involved, as coapplication of the D2 antagonist sulpiride (3 µM), together with quinpirole (10 µM), returned the mean evoked burst duration to values that did not differ significantly from control values.



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  		Figure 1. Activation of receptors in the D1 family increases regular, single spike driven firing in the subset of subthalamic neurons endowed with such capacity only. Top) Representative examples of regular, single spike-driven firing in a neuron that was not burst competent, as shown by the simultaneous termination of the stimulation (lower traces) and the voltage response (top traces) in each panels. The recording was made in the presence of synaptic transmission blockers (APV, 40 µM; CNQX, 10 µM; bicuculline, 10 µM) in this experiment as well as all others, and the membrane was hyperpolarized close to –80 mV by injecting a maintained hyperpolarizing current. The number of action potentials fired during the stimulation increased while SKF 82958 (5 µM), a specific agonist of dopamine receptors in the D1 family, was perfused. It returns to control frequency upon wash. Left) Box plot summary of the change in firing frequency with SKF 82958 and SKF 81297 (3–5 µM). The central line in the box shows the distribution median. The edges of the box are the interquartiles. The lines running from the edge of the box show the distribution extremes. The square display the mean. n, Number of experiments. Right, frequency-current relationship was shifted left in the same neuron sample.



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  		Figure 2. Activation of receptors in the D2 family promotes regular, single spike driven firing in the subset of subthalamic neurons endowed with the double capacity of burst- and regular, single spike firing. Top) Capacity to burst-firing was shown by the sustained action potential firing that markedly outlasted the stimulation. Such a regenerative firing is called plateau potential. The membrane was hyperpolarized by injecting a steady negative current. When quinpirole (10 µM), a specific agonist of dopamine receptors in the D2 family was perfused, the membrane depolarized and the plateau potential disappeared. Bringing the membrane back to its pre-test value (as indicated by the dotted line) by injecting a sustained hyperpolarizing current did not restore burst competency since a plateau potential was not obtained. Left) Box plots present the changes in the duration of and the number of action potentials in the discharge with quinpirole (10 µM) in a set of similar experiments on burst-competent neurons. Right) Distribution of the membrane potential values in the same neuron sample. Quinpirole (10 µM) significantly (P <0.001) depolarized the membrane.

Taken together, our results show that activating dopamine receptors strengthens regular, single spike firing. The fact that firing during depolarizing pulses was altered by dopamine agonists suggests that spontaneous firing might also be altered by dopamine receptor stimulation. Specifically, our data indicated that using quinpirole to activate receptors in the D2 family might prevent spontaneous burst-firing.

Indeed, we found that the spontaneous firing patterns were altered in the expected way. Perfusion of D1 agonists increased the spontaneous firing rate (6.35±1.45 Hz vs.4.15±0.77 Hz in control, n=12; three other neurons showed no change) without any other noticeable effect on the single spike discharge, including its regularity (see Fig. 3 ). In contrast, applying quinpirole to activate D2 receptors changed spontaneous burst-firing into tonic firing (Fig. 4 ). This was accompanied by a clear membrane depolarization (+7.6±0.9 mV, n=4; see the dotted line in Fig. 4 ). One neuron was found to be unresponsive to quinpirole, showing no change in firing pattern or depolarization.



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  		Figure 3. Agonists in the D1 family increase the discharge frequency of neurons that spontaneously discharge regular, single spikes. Top) Representative example of the action of an agonist in the D1 family, SKF 82358 (10 µM). The recording was made at zero current level. The bar above the record indicates the perfusion of the drug. Perfusion of SKF 38393 lastingly augmented the firing frequency (see the //, which corresponds to a 2 min interruption in the trace), with no other clear actions. Membrane potential remained unchanged (the dotted line shows the resting membrane potential). Bottom) Box plot summary of the change in firing frequency obtained with perfusion of D1 agonists (3–5 µM). All neurons were neurons that were not capable of burst-firing since they did not switch to burst-firing with negative current injection nor did they display a plateau potential with depolarizing stimuli.



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  		Figure 4. Activating receptors in the D2 family switch burst-firing to regular, single spike firing. Quinpirole (10 µM) was used to activate receptors in the D2 family in neurons that were spontaneously bursting at zero current level. It turned sustained burst-firing into regular, single spike firing. This was a persistent action (// indicates a 2 min interruption in the trace). The onset of change in firing pattern coincided with a small membrane depolarization, which was maintained in the same way as the new pattern.

In summary, these results show that agonists in the D1 and D2 families promote pacemaking in the STN in two ways: 1) by potentiating the firing frequency of neurons that only exhibit tonic firing capacity and 2) by a change in firing pattern that leads to tonic firing in burst-competent and spontaneously burst-firing neurons.


   FUNCTIONAL DOPAMINE RECEPTORS ARE EXPRESSED IN THE SUBTHALAMIC NUCLEUS
TOP
 ABSTRACT
 INTRODUCTION
 DOPAMINE RECEPTORS CONTROL...
 FUNCTIONAL DOPAMINE RECEPTORS...
D1 AND D2 RECEPTORS...
 DOPAMINE-DEPLETED STATE:...
 MATERIALS AND METHODS
 REFERENCES
 
At least two-thirds of the neurons are sensitive to dopamine agonists for each family of receptors. This suggests that a significant proportion of subthalamic neurons express functional receptors from both families. Subtype(s) in the D2 family have yet to be identified, as the D2 agonists currently available discriminate poorly between subtypes of receptors in this family. Considering that burst-competent neurons only express D5 (and not D1) receptors (34) , D5 and any of the D2/3/4 subtypes are likely to be coexpressed in a significant proportion of neurons.

Conversely, the relatively large number of neurons that are unresponsive to agonists in either family (one in three) suggests that differential responsiveness to dopamine constitutes a key feature of the STN.


   D1 AND D2 RECEPTORS PRODUCE SIMILAR CHANGES IN SUBTHALAMIC FIRING IN VITRO
TOP
 ABSTRACT
 INTRODUCTION
 DOPAMINE RECEPTORS CONTROL...
 FUNCTIONAL DOPAMINE RECEPTORS...
 D1 AND D2 RECEPTORS...
DOPAMINE-DEPLETED STATE:...
 MATERIALS AND METHODS
 REFERENCES
 
Figure 5 sums up all our findings. Activating receptors in the D1 family increases the frequency of tonic firing in pacemaking-only neurons (straight green arrow). This is also the case when D2 receptors are activated (45) . In addition, activating receptors in the D2 family has the crucial effect of turning burst-firing into a single spike firing pattern (rounded green arrow). Finally, D5 receptors potentiate burst-firing in burst-competent and spontaneously bursting subthalamic neurons (34, blue arrow).



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  		Figure 5. Actions of agonists of the dopamine receptors on firing in STN. Activation of receptors in the D1 and D2 families has assenting actions (green arrows), which eventually promotes regular, single spike firing. [1] Results of Zhu et al. (38) . Potentiation of burst-firing comes from activation of D5 receptors (blue arrow). [2] Results of Baufreton et al. (27) .

It was recently demonstrated that electrical stimulation in the STN evokes a significant dopamine release, supporting the possibility that the dopaminergic tone is sufficient to activate receptors in the D1 and D2 families (39) . We propose that, in the normal state, concurrent activation of receptors in the D1 and D2 families promotes tonic firing. As burst-firing is a prerequisite to D5 action, we contend that D2 activation leaves no substrate for the D5 burst-potentiating action. In the normal state, therefore, the repertoire of actions induced by activating dopamine receptors is restricted to those shown by the green arrows (Fig. 6 A). Activating receptors in the D1 and D2 families leads to different actions that, however, ultimately produce strengthened tonic firing. Moreover, the crucial action of D2 receptors turns spontaneously burst-firing neurons into pacemaking neurons, as well as helping to maintain burst-competent neurons in the tonic mode, thus preventing any major occurrence of burst-firing.



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  		Figure 6. Dopamine receptors set the pattern of activity generated in subthalamic neurons. A) Dopamine promotes regular, single spike firing receptors. In the normal state, dopamine activates receptors in the 2 families. However, activation of D2 receptors turns burst-firing into regular, single spike firing, thereby preventing any significant burst-potentiating action of D5 receptors. B) Dopamine depletion: emergence of burst-firing. In pathological states where dopamine levels are depressed, dopamine receptors are no longer activated by their natural ligand. As a consequence, the assenting actions of D1 and D2 receptors disappear. Regular, single spike firing is not promoted anymore. An exception to the lack of action of dopamine receptors is due to the high agonist-independent activity of D5 receptors. This causes burst-firing to come out.


   DOPAMINE-DEPLETED STATE: EMERGENCE OF BURST-FIRING
TOP
 ABSTRACT
 INTRODUCTION
 DOPAMINE RECEPTORS CONTROL...
 FUNCTIONAL DOPAMINE RECEPTORS...
 D1 AND D2 RECEPTORS...
 DOPAMINE-DEPLETED STATE:...
MATERIALS AND METHODS
 REFERENCES
 
When motor symptoms appear in patients and animal models of Parkinson’s disease, the death of nigral dopamine neurons is already massive, and basal dopamine tone in the striatum is very low (47) . A similar situation presumably occurs in the STN. The functional signature of D5 subtype receptors must be considered in this context. D5 receptors have the unique property of high agonist-independent constitutive activity (48 49 50 51) . While the synergistic action of D1 and D2 receptors is not expected to be maintained in a dopamine-depleted state, a significant part of the burst-potentiating action of D5 receptors persists, as indicated by the blue arrow (Fig. 6B ). This not only causes intrinsic burst properties to emerge but also strengthens them.

We suggest that the emergence of burst-firing to the detriment of tonic firing contributes to the changes in temporal and spatial firing patterns in the basal ganglia fundamental to the pathophysiology of movement. One possibility is that, in a dopamine-depleted state, burst-firing loses its relevance to information processing. Responses to synaptic events may become equivocal if they are superimposed on background burst-firing promoted by persistent activity of the D5 receptors despite the lack of dopamine. Whether this is the case of subthalamic responses to GABAergic pallidal inputs involving rebound bursts (30) remains to be seen. However, there is experimental evidence to indicate this may be the case for glutamatergic messages from the cortex. Indeed, cortical inputs activate group 1 metabotropic glutamate receptors that evoke burst-firing (26 , 28 , 29 , 52 , 53) . The two main afferent pathways to the STN may therefore interact with intrinsic mechanisms that evoke bursts. In addition, there may be some inappropriate neuronal synchronization in the indirect network that reverberates in other basal ganglia nuclei as a result of the powerful synaptic activity produced by burst discharges. No overt neuronal synchronization was found within the basal ganglia in one of the primate models of Parkinson’s disease (54) . However, task- and dopamine-related synchronized oscillatory activities have been recorded in several frequency domains, but their neural bases have not yet been elucidated (55) .

Bursting subthalamic neurons can be considered "inattentive" to synaptic inputs, in a way similar to bursting thalamocortical neurons. Dopamine converts burst-firing to single spike firing by causing a depolarization, thereby enabling subthalamic neurons to become "attentive" to synaptic inputs in the same way as activating neuromodulators in the thalamus. It is interesting to recall that whereas burst-firing coincides with bouts of slow-wave sleep in the STN of normal, nonanesthetized animals and is unaffected by GABA or glutamate receptors, it disappears in the waking state (56 , 57) . Our hypothesis that dopamine enables focused synaptic integration of the STN must now be challenged in animal models of Parkinson’s disease. This may be achieved at least partly by blocking the agonist-independent constitutive activity of D5 receptors in models derived from D1 and D5 knockout mice.

In summary, our studies suggest that D1- and D2-like dopamine receptors exert opposing influences on firing patterns in a subset of subthalamic neurons. Moreover, previous data suggest that D5 receptors may have constituent activity, therefore facilitating the burst-firing of subthalamic neurons in the absence of dopamine. We suggest that burst-firing may interfere with normal information processing, thus tending to exacerbate symptoms of Parkinson’s disease. As D5 receptors may be constituently active in the STN, strategies that down-regulate these receptors may prove to be beneficial in the treatment of Parkinson’s disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 DOPAMINE RECEPTORS CONTROL...
 FUNCTIONAL DOPAMINE RECEPTORS...
 D1 AND D2 RECEPTORS...
 DOPAMINE-DEPLETED STATE:...
 MATERIALS AND METHODS
REFERENCES
 
Slice preparation and electrophysiological recordings have been described thoroughly elsewhere (34 , 45) . Briefly, horizontal and coronal rat brain slices (300–400 µm thick) were used. Recordings were made using the blind patch-clamp technique in whole-cell configuration mode. Pipettes were filled with a solution containing (in mM): 130 K-gluconate and 10 mM NaCl, 11 EGTA, 10 HEPES, 1 CaCl2, 2 ATP-Mg, and 0.4 GTP-Na. In some experiments the main salt in the pipette medium was only K-gluconate (140 mM). APV (40 µM), CNQX (10 µM), and bicuculline methiodide (10 µM) were added to the Krebs solution and continuously perfused in order to block rapid synaptic transmission. All our recordings came from naive neurons. Once a slice had been perfused with any of the dopaminergic agonists listed below, it was discarded. SKF 82958, SKF 81297, and SKF 38393 were used as D1 agonists, whereas quinpirole was used as a D2 agonist. We found that the three D1 agonists had a similar action and pooled the results obtained with all three drugs. Unless stated otherwise, the term D1 agonists refers to these three drugs. The dopaminergic agonists were found to be specific to receptors in the D1 or D2 family for the following reasons: 1) coapplying any of the D1 agonists (3–5 µM) or the D1 antagonist SCH23390 (10 µM) had no effect, 2) applying quinpirole (10 µM) together with the D2 antagonist sulpiride (3 µM) was ineffective, and 3) the antagonists in the D1 or D2 families reversed the action of the agonists in each family. APV and quinpirole were purchased from Sigma (Saint Quentin Fallavier, France), CNQX, SKF 81297, SKF 82958, and SCH 23390 were purchased from RBI (Saint Quentin Fallavier, France). Bicuculline and SKF 38393 were obtained from Tocris (Bristol, UK).

Data analysis
Each neuron served as both control and test: spontaneous firing or driven firing in response to 3–5 increasingly depolarizing and hyperpolarizing steps were always recorded first in control, then in the presence of a dopaminergic agent. Percentage changes in the following parameters were calculated: spontaneous firing frequency, duration, and number of action potentials, as well as duration of plateau potentials, if appropriate. Absolute membrane potential values are given to reflect the small changes. All parameters were compared using the Wilcoxson matched-pairs signed ranks test. Values of P < 0.05 were considered significant. Box plots were used for graphic presentation of the data due to the small sample sizes. In the results, values are given as mean ± SE, when means are close to medians. Otherwise, median values are given. Figures show truncated spikes.


   ACKNOWLEDGMENTS
 
This work was funded by grants from CNRS, the USPHS (NS38715), University Victor Segalen, and the Aquitaine Region. J.B. received a doctoral fellowship from the Regional Council of Aquitaine. A.I.T. is on the Faculty of Pharmacy of the University V. Segalen.

Received for publication November 16, 2004. Accepted for publication August 3, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 DOPAMINE RECEPTORS CONTROL...
 FUNCTIONAL DOPAMINE RECEPTORS...
 D1 AND D2 RECEPTORS...
 DOPAMINE-DEPLETED STATE:...
 MATERIALS AND METHODS
 REFERENCES
 

  1. Steriade, M. (2000) Corticothalamic resonance, state of vigilance and mentation. Neuroscience 101,243-276[CrossRef][Medline]
  2. Steriade, M., McCormick, D. A., Sejnowski, T. J. (1993) Thalamocortical oscillations in the sleeping and aroused brain. Science 262,679-685[Abstract/Free Full Text]
  3. Steriade, M. (2001) To burst, or rather, not to burst. Nat. Neurosci. 4,671[CrossRef][Medline]
  4. Hartings, J. A., Temereanca, S., Simons, D. J. (2003) State-dependent processing of sensory stimuli by thalamic reticular neurons. J. Neurosci. 23,5264-5271[Abstract/Free Full Text]
  5. Lisman, J. E. (1997) Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 20,38-43[CrossRef][Medline]
  6. Eggermont, J. J. (1998) Is there a neural code?. Neurosci. Behav. Rev. 22,355-370[CrossRef][Medline]
  7. Sherman, S. M. (2001) Tonic and burst-firing: dual modes of thalamocortical relay. Trends Neurosci. 24,122-126[CrossRef][Medline]
  8. Krahe, R., Gabbiani, F. (2004) Burst-firing in sensory systems. Nat. Rev. Neurosci. 5,13-23[CrossRef][Medline]
  9. McCormick, D., Contreras, D. (2001) On the cellular and network bases of epileptic seizures. Annu. Rev. Physiol. 63,815-846[CrossRef][Medline]
  10. Albin, R. L., Young, A. B., Penney, J. B. (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci. 12,366-375[CrossRef][Medline]
  11. Crossman, A. R. (1990) A hypothesis on the pathophysiological mechanisms that underlie levodopa- or dopamine agonist-induced dyskinesia in Parkinson’s disease: Implications for future strategies in treatment. Mov. Disord. 5,100-108[CrossRef][Medline]
  12. Feger, J., Hassani, O.-K., Mouroux, M. (1997) The subthalamic nucleus and its connections. Adv. Neurol. 74,31-43[Medline]
  13. Krack, P., Pollak, P., Limousin, P., Benazzouz, A., Deuschl, G., Benabid, A.-L. (1999) From off-period dystonia to peak-dose chorea: the clinical spectrum of varying subthalamic nucleus activity. Brain 122,1133-1146[Abstract/Free Full Text]
  14. Nutt, J. G., Rufener, S. L., Carter, J. H., Anderson, V. C., Pahwa, R., Hammerstad, J. P., Burchiel, K. J. (2001) Interactions between deep brain stimulation and levodopa in Parkinson’s disease. Neurology 57,1835-1842[Abstract/Free Full Text]
  15. Parent, A., Hazrati, L.-N. (1995) Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res. Rev. 20,128-154[CrossRef][Medline]
  16. Bergman, H., Wichmann, T., Karmon, B., DeLong, M. R. (1994) The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J. Neurophysiol. 72,507-520[Abstract/Free Full Text]
  17. Hollerman, J. R., Grace, A. A. (1992) Subthalamic nucleus cell firing in the 6-OHDA-treated rat: basal activity and response to haloperidol. Brain Res. 590,291-299[CrossRef][Medline]
  18. Overton, P. G., Greenfield, S. A. (1995) Determinants of neuronal firing pattern in the guinea-pig subthalamic nucleus: an in vivo and in vitro comparison. J. Neural Transm. 10,41-54
  19. Hassani, O.-K., Mouroux, M., Feger, J. (1996) Increased subthalamic nucleus neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus. Neuroscience 72,105-115[CrossRef][Medline]
  20. Hassani, O. K., Feger, J. (1999) Effects of intrasubthalamic injection of dopamine receptor agonists on subthalamic neurons in normal and 6-hydroxydopamine-lesioned rats: an electrophysiological and c-Fos study. Neuroscience 92,533-543[CrossRef][Medline]
  21. Ni, Z. G., Bouali-Benazzouz, R., Gao, D. M., Benabid, A. L., Benazzouz, A. (2001) Time-course of changes in firing rates and firing patterns of subthalamic nucleus neuronal activity after 6-OHDA-induced dopamine depletion in rats. Brain Res. 899,142-147[CrossRef][Medline]
  22. Benedetti, F., Colloca, L., Torre, E., Lanotte, M., Melcarne, A., Pesare, M., Bergamasco, B., Lopiano, L. (2004) Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci. 7,587-588[CrossRef][Medline]
  23. Song, W. J., Baba, Y., Otsuka, T., Murukami, F. (2000) Characterization of Ca2+ channels in rat subthalamic nucleus neurons. J. Neurophysiol. 84,2630-2637[Abstract/Free Full Text]
  24. Beurrier, C., Congar, P., Bioulac, B., Hammond, C. (1999) Subthalamic nucleus neurons switch from single-spike activity to burst-firing mode. J. Neurosci. 19,599-609[Abstract/Free Full Text]
  25. Awad, H., Hubert, G. W., Smith, Y., Levey, A. I., Conn, P. J. (2000) Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J. Neurosci. 20,7871-7879[Abstract/Free Full Text]
  26. Do, M. T., Bean, B. P. (2003) Subthreshold sodium currents and pacemaking of subthalamic neurons: modulation by slow inactivation. Neuron 39,109-120[CrossRef][Medline]
  27. Zhu, Z. T., Munhall, A., Shen, K. Z., Johnson, S. W. (2004) Calcium-dependent subthreshold oscillations determine bursting activity induced by N-methyl-D-aspartate in rat subthalamic neurons in vitro. Eur. J. Neurosci. 19,1296-1304[CrossRef][Medline]
  28. Hallworth, N. E., Wilson, C. J., Bevan, M. D. (2003) Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nucleus neurons in vitro. J. Neurosci. 23,7525-7542[Abstract/Free Full Text]
  29. Otsuka, T., Murakami, F., Song, W. J. (2001) Excitatory postsynaptic potentials trigger a plateau potential in rat subthalamic neurons at hyperpolarized states. J. Neurophysiol. 86,1816-1825[Abstract/Free Full Text]
  30. Bevan, M. D., Magill, P. J., Hallworth, N. E., Bolam, J. P., Wilson, C. J. (2002) Regulation of the timing and pattern of action potential generation in rat subthalamic neurons in vitro by GABA-A IPSPs. J. Neurophysiol. 87,1348-1362[Abstract/Free Full Text]
  31. Nakanishi, H., Kita, H., Kitai, S. T. (1987) Electrical membrane properties of rat subthalamic neurons in an in vitro slice preparation. Brain Res. 437,35-44[CrossRef][Medline]
  32. Bevan, M. D., Wilson, C. J., Bolam, J. P., Magill, P. J. (2000) Equilibrium potential of GABA(A) current and implications for rebound burst-firing in rat subthalamic neurons in vitro. J. Neurophysiol. 83,3169-3172[Abstract/Free Full Text]
  33. Baufreton, J., Garret, M., Dovero, S., Dufy, B., Bioulac, B., Taupignon, A. (2001) Activation of GABA(A) receptors in subthalamic neurons in vitro: properties of native receptors and inhibition mechanisms. J. Neurophysiol. 86,75-85[Abstract/Free Full Text]
  34. Baufreton, J., Garret, M., Rivera, A., de la Calle, A., Gonon, F., Dufy, B., Bioulac, B., Taupignon, A. (2003) D5 (not D1) dopamine receptors potentiate burst-firing in neurons of the subthalamic nucleus by modulating an L-type calcium conductance. J. Neurosci. 23,816-825[Abstract/Free Full Text]
  35. Wichmann, T., DeLong, M. R. (2003) Pathophysiology of Parkinson’s disease: the MPTP primate model of the human disorder. Ann. N.Y. Acad. Sci. 991,199-213[Abstract/Free Full Text]
  36. Brown, L. L., Markman, M. H., Wolfson, L. I., Dvorkin, B., Warner, C., Katzman, R. (1979) A direct role of dopamine in the rat subthalamic nucleus and an adjacent intrapeduncular area. Science 206,1416-1418[Abstract/Free Full Text]
  37. Hassani, O. K., Francois, C., Yelnik, J., Feger, J. (1997) Evidence for a dopaminergic innervation of the subthalamic nucleus in the rat. Brain Res. 749,88-94[CrossRef][Medline]
  38. Francois, C., Savy, C., Jan, C., Tande, D., Hirsch, E. C., Yelnik, J. (2000) Dopaminergic innervation of the subthalamic nucleus in the normal state, in MPTP-treated monkeys, and in Parkinson’s disease patients. J. Comp. Neurol. 425,121-129[CrossRef][Medline]
  39. Cragg, S. J., Baufreton, J., Xue, Y., Bolam, J. P., Bevan, M. D. (2004) Restricted, synaptic release of dopamine in the subthamic nucleus of the rat. Synaptic release of dopamine in the subthalamic nucleus. Eur. J. Neurosci. 20,1788-1802[CrossRef][Medline]
  40. Missale, C., Nash, S. R., Robinson, S. W., Jaber, M., Caron, M. G. (1998) Dopamine receptors: from structure to function. Physiol. Rev. 78,189-225[Abstract/Free Full Text]
  41. Kreiss, D. S., Anderson, L. A., Walters, J. R. (1996) Apomorphine and dopamine D(1) receptor agonists increase the firing rates of subthalamic nucleus neurons. Neuroscience 72,863-876[CrossRef][Medline]
  42. Kreiss, D. S., Mastropietro, C. W., Rawji, S. S., Walters, J. R. (1997) The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson’s disease. J. Neurosci. 17,6807-6819[Abstract/Free Full Text]
  43. Mehta, A., Thermos, K., Chesselet, M. F. (2000) Increased behavioral response to dopaminergic stimulation of the subthalamic nucleus after nigrostriatal lesions. Synapse 37,298-307[CrossRef][Medline]
  44. Svenningsson, P., Le Moine, C. (2002) Dopamine D1/5 receptor stimulation induces c-fos expression in the subthalamic nucleus: possible involvement of local D5 receptors. Eur. J. Neurosci. 15,133-142[CrossRef][Medline]
  45. Zhu, Z. T., Bartol, M., Shen, K. Z., Johnson, S. W. (2002) Pharmacological identification of inward current evoked by dopamine in rat subthalamic neurons in vitro. Neuropharmacology 42,772-781[CrossRef][Medline]
  46. Zhu, Z. T., Bartol, M., Shen, K. Z., Johnson, S. W. (2002) Excitatory effects of dopamine on rat subthalamic neurons: in vitro study of rats pretreated with 6-hydroxydopamine and levodopa. Neuropharmacology 42,772-781
  47. Bezard, E., Dovero, S., Prunier, C., Ravenscroft, P., Chalon, S., Guilloteau, D., Crossman, A. R., Bioulac, B., Brotchie, J. M., Gross, C. E. (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J. Neurosci. 21,6853-6861[Abstract/Free Full Text]
  48. Tiberi, M., Caron, M. G. (1994) High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype. J. Biol. Chem. 269,27925-27931[Abstract/Free Full Text]
  49. Demchyshyn, L. L., McConkey, F., Niznik, H. B. (2000) Dopamine D5 receptor agonist high affinity and constitutive activity profile conferred by carboxyl-terminal tail sequence. J. Biol. Chem. 275,23446-23455[Abstract/Free Full Text]
  50. Jackson, A., Iwasiow, R. M., Tiberi, M. (2000) Distinct function of the cytoplasmic tail in human D1-like receptor ligand binding and coupling. FEBS Lett. 470,183-188[CrossRef][Medline]
  51. Tumova, K., Iwasiow, R. M., Tiberi, M. (2003) Insight into the mechanism of dopamine D1-like receptor activation. Evidence for a molecular interplay between the third extracellular loop and the cytoplasmic tail. J. Biol. Chem. 278,8146-8153[Abstract/Free Full Text]
  52. Magill, P. J., Bolam, J. P., Bevan, M. D. (2001) Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network. Neuroscience 106,313-330[CrossRef][Medline]
  53. Marino, M. J., Awad-Granko, H., Ciombor, K. J., Conn, P. J. (2002) Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata. Neuropharmacology 43,147-159[CrossRef][Medline]
  54. Levy, R., Hutchison, W. D., Lozano, A. M., Dostrovsky, J. O. (2002) Synchronized neuronal discharge in the basal ganglia of parkinsonian patients is limited to oscillatory activity. J. Neurosci. 22,2855-2861[Abstract/Free Full Text]
  55. Hutchison, W. D., Dostrovsky, J. O., Walters, J. R., Courtemanche, R., Boraud, T., Goldberg, J., Brown, P. (2004) Neuronal oscillations in the basal ganglia and movement disorders: evidence from whole animal and human recordings. J. Neurosci. 24,9240-9243[Free Full Text]
  56. Urbain, N., Rentero, N., Gervasoni, D., Renaud, B., Chouvet, G. (2002) The switch of subthalamic neurons from an irregular to a bursting pattern does not solely depend on their GABAergic inputs in the anesthetic-free rat. J. Neurosci. 22,8665-8675[Abstract/Free Full Text]
  57. Urbain, N., Vautrelle, N., Dahan, L., Savasta, M., Chouvet, G. (2004) Glutamatergic-receptors blockade does not regularize the slow wave sleep bursty pattern of subthalamic neurons. Eur. J. Neurosci. 20,392-402[CrossRef][Medline]



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