Electrophysiological Correlates of a Versatile Executive Control System in the Monkey Anterior Cingulate Cortex.

When a subject faces conflicting situations, decision-making becomes uncertain. The human dorsal anterior cingulate cortex (dACC) has been repeatedly implicated in the monitoring of such situations, and its neural activity is thought to be involved in behavioral adjustment. However, this hypothesis is mainly based on neuroimaging results and is challenged by animal studies that failed to report any neuronal correlates of conflict monitoring. This discrepancy is thought be due either to methodological or more fundamental cross-species differences. In this study, we eliminated methodological biases and recorded single-neuron activity in monkeys performing a Stroop-like task. We found specific changes in dACC activity during incongruent trials but only in a small subpopulation of cells. Critically, these changes were not related to reaction time and were absent before any incorrect action was taken. A larger fraction of neurons exhibited sustained activity during the whole decision period, whereas another subpopulation of neurons was modulated by reaction time, with a gradual increase in their firing rate that peaked at movement onset. Most of the neurons found in these subpopulations exhibited activity after the delivery of an external negative feedback stimulus that indicated an error had been made. These findings, which are consistent with an executive control role, reconcile various theories of prefrontal cortex function and support the homology between human and monkey cognitive architectures.

Inhibiting subthalamic D5 receptor constitutive activity alleviates abnormal electrical activity and reverses motor impairment in a rat model of Parkinson's disease.

Burst firing has been reported as a pathological activity of subthalamic nucleus (STN) neurons in Parkinson's disease. However, the origin of bursts and their causal link with motor deficits remain unknown. Here we tested the hypothesis that dopamine D5 receptors (D5Rs), characterized by a high constitutive activity, may contribute to the emergence of burst firing in STN. We tested whether inhibiting D5R constitutive activity depresses burst firing and alleviates motor impairments in the 6-OHDA rat model of Parkinson's disease. Intrasubthalamic microinjections of either an inverse agonist of D5Rs, flupenthixol, or a D2R antagonist, raclopride, were applied. Behavioral experiments, in vivo and in vitro electrophysiological recordings, and ex vivo functional neuroanatomy studies were performed. Using [(5)S]GTPγ binding autoradiography, we show that application of flupenthixol inhibits D5R constitutive activity within the STN. Furthermore, flupenthixol reduced evoked burst in brain slices and converted pathological burst firing into physiological tonic, single-spike firing in 6-OHDA rats in vivo. This later action was mimicked by calciseptine, a Cav1 channel blocker. Moreover, the same treatment dramatically attenuated motor impairment in this model and normalized metabolic hyperactivity in both STN and substantia nigra pars reticulata, the main output structure of basal ganglia in rats. In contrast, raclopride as well as saline did not reverse burst firing and motor deficits, confirming the selective action of flupenthixol on D5Rs. These results are the first to demonstrate that subthalamic D5Rs are involved in the pathophysiology of Parkinson's disease and that administering an inverse agonist of these receptors may lessen motor symptoms.

Dopamine-dependent long-term depression at subthalamo-nigral synapses is lost in experimental parkinsonism.

Impairments of synaptic plasticity are a hallmark of several neurological disorders, including Parkinson's disease (PD) which results from the progressive loss of dopaminergic neurons of the substantia nigra pars compacta leading to abnormal activity within the basal ganglia (BG) network and pathological motor symptoms. Indeed, disrupted plasticity at corticostriatal glutamatergic synapses, the gateway of the BG, is correlated to the onset of PD-related movement disorders and thus has been proposed to be a key neural substrate regulating information flow and motor function in BG circuits. However, a critical question is whether similar plasticity impairments could occur at other glutamatergic connections within the BG that would also affect the inhibitory influence of the network on the motor thalamus. Here, we show that long-term plasticity at subthalamo-nigral glutamatergic synapses (STN-SNr) sculpting the activity patterns of nigral neurons, the main output of the network, is also affected in experimental parkinsonism. Using whole-cell patch-clamp in acute rat brain slices, we describe a molecular pathway supporting an activity-dependent long-term depression of STN-SNr synapses through an NMDAR-and D1/5 dopamine receptor-mediated endocytosis of synaptic AMPA glutamate receptors. We also show that this plastic property is lost in an experimental rat model of PD but can be restored through the recruitment of dopamine D1/5 receptors. Altogether, our findings suggest that pathological impairments of subthalamo-nigral plasticity may enhance BG outputs and thereby contribute to PD-related motor dysfunctions.

Long-term depression at distinct glutamatergic synapses in the basal ganglia.

Long-term adaptations of synaptic transmission are believed to be the cellular basis of information storage in the brain. In particular, long-term depression of excitatory neurotransmission has been under intense investigation since convergent lines of evidence support a crucial role for this process in learning and memory. Within the basal ganglia, a network of subcortical nuclei forming a key part of the extrapyramidal motor system, plasticity at excitatory synapses is essential to the regulation of motor, cognitive, and reward functions. The striatum, the main gateway of the basal ganglia, receives convergent excitatory inputs from cortical areas and transmits information to the network output structures and is a major site of activity-dependent plasticity. Indeed, long-term depression at cortico-striatal synapses modulates the transfer of information to basal ganglia output structures and affects voluntary movement execution. Cortico-striatal plasticity is thus considered as a cellular substrate for adaptive motor control. Downstream in this network, the subthalamic nucleus and substantia nigra nuclei also receive glutamatergic innervation from the cortex and the subthalamic nucleus, respectively. Although these connections have been less investigated, recent studies have started to unravel the molecular mechanisms that contribute to adjustments in the strength of cortico-subthalamic and subthalamo-nigral transmissions, revealing that adaptations at these synapses governing the output of the network could also contribute to motor planning and execution. Here, we review our current understanding of long-term depression mechanisms at basal ganglia glutamatergic synapses and emphasize the common and unique plastic features observed at successive levels of the network in healthy and pathological conditions.

Altered pallido-pallidal synaptic transmission leads to aberrant firing of globus pallidus neurons in a rat model of Parkinson's disease.

The pattern of activity of globus pallidus (GP) neurons is tightly regulated by GABAergic inhibition. In addition to extrinsic inputs from the striatum (STR-GP) the other source of GABA to GP neurons arises from intrinsic intranuclear axon collaterals (GP-GP). While the contribution of striatal inputs has been studied, notably its hyperactivity in Parkinson's disease (PD), the properties and function of intranuclear inhibition remain poorly understood. Our objective was therefore to test the impact of chronic dopamine depletion on pallido-pallidal transmission. Using patch-clamp whole-cell recordings in rat brain slices, we combined electrical and optogenetic stimulations with pharmacology to differentiate basic synaptic properties of STR-GP and GP-GP GABAergic synapses. GP-GP synapses were characterized by activity-dependent depression and insensitivity to the D(2) receptor specific agonist quinpirole and STR-GP synapses by frequency-dependent facilitation and quinpirole modulation. Chronic dopamine deprivation obtained in 6-OHDA lesioned animals boosted the amplitude of GP-GP IPSCs but did not modify STR-GP transmission and increased the amplitude of miniature IPSCs. Replacement of calcium by strontium confirmed that the quantal amplitude was increased at GP-GP synapses. Finally, we demonstrated that boosted GP-GP transmission promotes resetting of autonomous activity and rebound-burst firing after dopamine depletion. These results suggest that GP-GP synaptic transmission (but not STR-GP) is augmented by chronic dopamine depletion which could contribute to the aberrant GP neuronal activity observed in PD.

Evolution of the dynamic properties of the cortex-basal ganglia network after dopaminergic depletion in rats.

It is well established that parkinsonian syndrome is associated with alterations of neuronal activity temporal pattern basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in Parkinson's disease patients as well as animal models such as 6-hydroxydopamine treated rats. We recently demonstrated that this increase in oscillatory synchronization is present during high-voltage spindles (HVS) probably underpinned by the disorganization of cortex-BG interactions. Here we investigated the time course of both oscillatory and motor alterations. For that purpose we performed daily simultaneous recordings of neuronal activity in motor cortex, striatum and substantia nigra pars reticulata (SNr), before and after 6-hydroxydopamine lesion in awake rats. After a brief non-dopamine-specific desynchronization, oscillatory activity first increased during HVS followed by progressive motor impairment and the shortening of SNr activation delay. While the oscillatory firing increase reflects dopaminergic depletion, response alteration in SNr neurons is closely related to motor symptom.

Check or Go? Impact of Doubt on the Hierarchical Organization of the Mediofrontal Area.

BACKGROUND: Based on numerous imaging and electrophysiological studies, the presupplementary motor area (pre-SMA) and the rostral cingulate motor area are cortical regions considered to be essential to voluntary movement initiation and behavioral control. However, their respective roles and functional interactions remain a long-standing and still debated question. METHODS: Here, we trained 2 rhesus monkeys (Macaca mulatta) in a complex cognitive task to compare the neuronal activity of these 2 regions on the medial wall during both perceptual and internally guided decisions. RESULTS: We confirmed the implication of both areas throughout the decision process. Critically, we demonstrate that instead of a stable invariant role, the pre-SMA and rostral cingulate motor area manifested a versatile hierarchical relationship depending on the mode of movement initiation. Whereas pre-SMA neurons were primarily engaged in decisions based on perceptual information, rostral cingulate motor area neurons preempted the decision process in case of an internally doubt-driven checking behavior, withholding pre-SMA recruitment during the time spent inhibiting the habitual action. CONCLUSIONS: We identified a versatile hierarchical organization of the mediofrontal area that may substantially affect normal and pathological decision processes because adaptive behaviors, such as doubt-checking and its compulsive counterpart, rely on this subtle equilibrium in controlling action initiation.

High-frequency stimulation of the subthalamic nucleus and L-3,4-dihydroxyphenylalanine inhibit in vivo serotonin release in the prefrontal cortex and hippocampus in a rat model of Parkinson's disease.

High-frequency stimulation of the subthalamic nucleus (STN-HFS) and l-3,4-dihydroxyphenylalanine (l-DOPA) medication are the most used therapeutic approaches in Parkinson's disease (PD), but their beneficial motor effects are burdened by the emergence of cognitive and depressive disorders. Although a reduced serotonergic function has been linked to the psychiatric effects of antiparkinsonian treatments, biochemical evidence supporting this hypothesis is still lacking. By using a microdialysis approach in anesthetized rats, we investigated the ability of STN-HFS (130 Hz, 30 muA, 20 min) and l-DOPA (6-12 mg/kg) to change extracellular levels of serotonin (5-HT) monitored simultaneously in the prefrontal cortex (PFC) and hippocampus (HIPP), two brain regions involved in the regulation of mood and cognition that receive a distinct 5-HT innervation. The results show that STN-HFS inhibited 5-HT levels in the PFC and HIPP of sham-lesioned and 6-hydroxydopamine (6-OHDA)-lesioned rats. The effect elicited by STN-HFS was blocked by the administration of the 5-HT(1A) agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin. l-DOPA (6 and 12 mg/kg) reduced 5-HT levels in the PFC and HIPP of 6-OHDA rats. STN-HFS did not further decrease 5-HT levels induced by l-DOPA, but attenuated l-DOPA-induced dopamine release in the PFC and HIPP. These neurochemical data show that STN-HFS inhibits 5-HT release by modulating serotonergic neuron activity, while the decrease in 5-HT levels induced by l-DOPA may include its direct action inside serotonergic neurons. These results support the premise that antiparkinsonian treatments reduce central serotonergic transmission, which may favor the development of nonmotor side effects in PD.

Chronic L-DOPA therapy alters central serotonergic function and L-DOPA-induced dopamine release in a region-dependent manner in a rat model of Parkinson's disease.

The therapeutic benefit of L-DOPA is commonly attributed to restoration of dopamine (DA) extracellular levels in the striatum of Parkinsonian patients. However, the loss of efficacy of L-DOPA after chronic use is paradoxically associated with a similar or enhanced striatal DA response. Release of L-DOPA-derived DA depends on the widespread serotonergic (5-HT) innervation in the brain. Chronic exposure of 5-HT neurons to L-DOPA could lead to aberrant neurochemical responses beyond the striatum. Using multi-site intracerebral microdialysis in a rat model of Parkinson's disease, we showed that chronic L-DOPA treatment at a therapeutic dose (12 mg/kg/day for 10 days) homogeneously reduced basal 5-HT release and metabolism. These effects were paralleled by a decrease in tissue content of 5-HT and its metabolite. Chronic L-DOPA treatment severely altered the brain pattern of 5-HT and DA release responses to L-DOPA (3-12 mg/kg) with an overall loss of efficacy of L-DOPA to increase DA release. Our data demonstrate for the first time in vivo that the impairment of 5-HT neuronal function induced by chronic L-DOPA alters in a region-dependent manner L-DOPA-induced DA release. Changes in neurochemical pattern of L-DOPA in the brain may favour the occurrence of both motor and non-motor side effects.

Primate models of dystonia.

Several models of dystonia have emerged from clinical studies providing a comprehensive explanation for the pathophysiology of this movement disorder. However, several points remain unclear notably concerning the specific role of brainstem, basal ganglia nuclei and premotor cortex. We review data collected in sub-human primate to see whether they might provide new insights into the pathophysiology of dystonia. As in human patients, lesions of the putamen induce dystonia, as well as pharmacological manipulations of the dopaminergic system. In addition, primate studies revealed that lesions in brain stem areas involved in the control of muscular tone and GABAergic manipulations in various basal ganglia nuclei or thalamus also lead to dystonia. Moreover, there is a dramatic disruption in the processing of proprioceptive information with abnormal large receptive fields in the basal ganglia, thalamus, primary somesthetic cortex and premotor cortex of dystonic monkeys. These data highlight the idea that dystonia is associated with aberrant sensory representations interfering with motor control. Considering that the supplementary motor area (SMAp) is the target of basal ganglia projections within the motor loop, we propose a model of dystonia in which abnormal excitability, associated with alteration in sensory receptive fields within the SMAp, leads to an abnormal synchronization between primary motor cortex columns. Such a phenomenon might account for the co-contractions of antagonist muscles favored by action and the abnormal postures observed in dystonia.

The relationship between insight and uncertainty in obsessive-compulsive disorder.

BACKGROUND: The aim of this study was to investigate the relationship between the levels of insight and checking-related uncertainty in patients with obsessive-compulsive disorder (OCD). SAMPLING AND METHODS: Twenty OCD patients with checking compulsions and without current comorbidity were recruited. We used an experimental paradigm that gave subjects the opportunity to check during a decision-making task, thereby allowing for the calculation of a response time index (RTI) as the 'uncertainty cost' during decision-making. The level of insight was assessed with the Brown Assessment of Beliefs Scale (BABS). RESULTS: Regression analyses indicated a significant positive correlation between RTI and BABS scores (r = 0.49). CONCLUSIONS: The level of insight is related to cognitive characteristics underlying OCD symptoms, in particular, checking-related uncertainty in checking OCD patients. STUDY LIMITATIONS: The absence of a comparison group and the low number of included patients are the main limitations of the present study.

Serotonergic neurons mediate ectopic release of dopamine induced by L-DOPA in a rat model of Parkinson's disease.

Benefit and motor side effects of l-DOPA in Parkinson's disease have been related to dopamine transmission in the striatum. However, the putative involvement of serotonergic neurons in the dopaminergic effects of l-DOPA suggests that the striatum is not a preferential target of l-DOPA. By using microdialysis in a rat model of Parkinson's disease, we found that l-DOPA (3-100 mg/kg) increased dopamine extracellular levels monitored simultaneously in four brain regions receiving serotonergic innervation: striatum, substantia nigra, hippocampus, prefrontal cortex. The increase was regionally similar at the lowest dose and 2-3 times stronger in the striatum at higher doses. Citalopram, a serotonin reuptake blocker, or the destruction of serotonergic fibers by 5,7-dihydroxytryptamine impaired l-DOPA-induced dopamine release in all regions. These data demonstrate that l-DOPA induces an ectopic release of dopamine due to serotonergic neurons. The new pattern of dopamine transmission created by l-DOPA may contribute to the benefit and side effects of l-DOPA.

Genes regulated in MPTP-treated macaques and human Parkinson's disease suggest a common signature in prefrontal cortex.

The presymptomatic phase of Parkinson's disease (PD) is now recognized as a prodromal phase, with compensatory mechanism masking its progression and non-motor early manifestations, such as depression, cognitive disturbances and apathy. Those mechanisms were thought to be strictly dopamine-mediated until recent advances have shed light upon involvement of putative outside-basal ganglia, i.e. cortical, structures. We took advantage of our progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model to monitor whole genome transcriptional changes in several brain areas. Our data reveals that transcriptomic activity changes take place from early stages, suggesting very early compensatory mechanisms or pathological activity outside the basal ganglia, including the PFC. Specific transcriptomic changes occurring in the PFC of fully parkinsonian MPTP-treated macaques have been identified. Interestingly, a large part of these transcriptomic changes were also observed in human post-mortem samples of patients with neurodegenerative diseases analysed by quantitative PCR. These results suggest that the PFC is able to detect the progression of dopamine denervation even at very early time points. There are therefore mechanisms, within the PFC, leading to compensatory alterations and/or participating to pathophysiology of prodromal PD manifestations.

Sleepiness, near-misses and driving accidents among a representative population of French drivers.

Study objectives were to determine the prevalence of sleepy driving accidents and to explore the factors associated with near-miss driving accidents and actual driving accidents in France. An epidemiological survey based on telephone interviews was conducted on a representative sample of French drivers. The questionnaire included sociodemographics, driving and sleep disorder items, and the Epworth sleepiness scale. Of 4774 drivers (response rate: 86%), 28% experienced at least one episode of severe sleepiness at the wheel (i.e. requiring to stop driving) in the previous year; 11% of drivers reported at least one near-miss accident in the previous year (46% sleep-related); 5.8% of drivers reported at least one accident, 5.2% of these being sleep related (an estimate of 90,000 sleep-related accidents per year in France). Sleepy driving accidents occurred more often in the city (53.8%), during short trips (84.6%) and during the day (84.6%). Using logistic regression, the best predictive factor for near-misses was the occurrence of at least one episode of severe sleepiness at the wheel in the past year [odds ratio (OR) 6.50, 95% confidence interval (CI), 5.20-8.12, P < 0.001]. The best predictive factors for accidents were being young (18-30 years; OR 2.13, 95% CI, 1.51-3.00, P < 0.001) and experiencing at least one episode of severe sleepiness at the wheel (OR 2.03, 95% CI, 1.57-2.64, P < 0.001). Sleepiness at the wheel is a risk factor as important as age for traffic accidents. Near-misses are highly correlated to sleepiness at the wheel and should be considered as strong warning signals for future accidents.

Maintenance of Wakefulness Test, obstructive sleep apnea syndrome, and driving risk.

OBJECTIVE: Sleepiness at the wheel is a major risk factor for traffic accidents. Because of the potential medical and legal implications, in this study, we evaluated the correlation between subjective and objective measures of sleepiness and driving performances in patients suffering from excessive daytime sleepiness. METHODS: Thirty-eight untreated sleep apnea patients (mean age +/- standard deviation, 51 +/- 9 years; mean apnea-hypopnea index +/- standard deviation, 41 +/- 25), and 14 healthy control subjects (mean age +/- standard deviation, 46 +/- 9 years) were included in the study. Nocturnal polysomnography, mean sleep latency as measured by four 40-minute Maintenance of Wakefulness Test (MWT) trials, Epworth Sleepiness Scale, Karolinska Sleepiness Scale, and the number of inappropriate line crossings during a 90-minute real-life driving session were analyzed. RESULTS: The number of inappropriate line crossings correlated with MWT scores (Spearman's Rho: r = -0.339; p < 0.05), Karolinska Sleepiness Scale scores measured at halfway in total driving distance (Rho: r = 0.367; p < 0.01), and Epworth Sleepiness Scale (Rho: r = 0.389; p < 0.01). We found a significant difference in the number of inappropriate line crossings among the four groups defined by MWT scores (very sleepy [0-19 minutes], sleepy [20-33 minutes], alert [34-40 minutes], and controls) (Kruskal-Wallis test: H = 11.319; p < 0.01). Very sleepy and sleepy patients had more inappropriate line crossings than the control drivers (p < 0.05). INTERPRETATION: In addition to subjective sleepiness scales, the MWT can be used to assess driving ability in untreated sleep apnea patients.

Impact of commitment on performance evaluation in the rostral cingulate motor area.

Performance evaluation is a prerequisite for behavioral adaptation. Although the anterior cingulate cortex (ACC) is thought to play a central role in error detection, little is known about the electrophysiological activity of this structure during the performance-monitoring process. We directly addressed this issue by training monkeys to perform a Stroop-like task and then recorded neuronal activity in the rostral cingulate motor area (CMAr), a relatively unexplored region of the ACC known to be involved in motor processing. We found that most CMAr neurons responded during the evaluation period to both positive and negative feedback, but neuronal changes were more important after an error than after a successful trial. Interestingly, this performance-monitoring activity was not directly modulated by the degree of difficulty of the cognitive situation because changes in discharge frequency were similar whatever the level of attentional control imposed on the monkey. Firing activity during the evaluation period increased more, however, in erroneously completed than in incompleted trials and when the reward was delivered in an active rather than passive context, indicating that performance evaluation was conditioned by the degree of commitment of the animal to the task. It would thus seem that CMAr neurons could constitute a system for the evaluation of behavioral performance contingent on the subject's commitment to the task.

Noradrenergic modulation of subthalamic nucleus activity: behavioral and electrophysiological evidence in intact and 6-hydroxydopamine-lesioned rats.

The subthalamic nucleus (STN) plays a key role in the pathophysiology of Parkinson's disease. The modulation of the STN by norepinephrine, however, is unknown. The present study aims at characterizing the effects of systemic administration of noradrenergic agents on locomotor activity and on in vivo extracellularly recorded STN neuronal activity in intact and 6-hydroxydopamine (6-OHDA)-lesioned rats. Using selective agonists and antagonists of alpha1 and alpha2 adrenergic receptors (ARs), we show that STN neurons have functional alpha1- and alpha2-AR controlling STN firing with an impact on locomotor activity. We further demonstrate that those systemic effects are supported, at least in part, by a direct modulation of STN neuronal activity, using patch-clamp recordings of STN neurons in brain slices. These findings support the premise that hypokinesia is associated with an increased STN neuronal activity, and that improvements of parkinsonian motor abnormalities are associated with a decrease in STN activity. Our data challenge assumptions about the role of alpha1-AR and alpha2-AR in the regulation of STN neurons in both intact and 6-OHDA-lesioned rats and further ground the rationale for using alpha2-AR noradrenergic antagonists in Parkinson's disease, albeit via an unexpected mechanism.

Shaping of motor responses by incentive values through the basal ganglia.

The striatum is a key neural interface for cognitive and motor information processing in which associations between reward value and visual stimulus can be used to modify motor commands. It can guide action-selection processes that occur farther downstream in the basal ganglia (BG) circuit, by encoding the reward value of an action. Here, we report on the study of simultaneously recorded neurons in the dorsal striatum (input stage of the BG) and the internal pallidum (output stage of the BG) in two monkeys performing a center-out motor task in which the visual targets were associated with different reward probabilities. We show that the tuning curves of motor-related neurons in both structures are modulated by the value of the action before movement initiation and during its execution. The representations of values associated with different actions change dynamically during the task in the internal globus pallidus, with a significant increase in the number of encoding neurons for the chosen target at the onset of movement. This report sheds additional light on the functional differences between the input and output structures of the BG and supports the assertion that the dorsal basal ganglia are involved in movement-related decision-making processes based on incentive values.

RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson's disease.

Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9-2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9-/- mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9+/+ mice, albeit the rotational behavior--taken as an index of the anti-parkinsonian response--is similar between the two groups of mice. Together, these findings suggest that RGS9-2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9-2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.