Biomedical subjects

Christelle Baunez

Publications and source records attributed to Christelle Baunez.

12 recordsLinked to original sources

PubMed2006

The dopamine agonist piribedil with L-DOPA improves attentional dysfunction: relevance for Parkinson's disease.

Cognitive deficits are often associated with motor symptoms in Parkinson's disease. This study investigates the ability of piribedil ([(methylenedioxy-3,4 benzyl)-4 pyperazinyl-1]-2 pyrimidine), a D(2)/D(3) dopamine (DA) receptor agonist with antagonist activity at alpha(2A)-adrenoceptors, to restore motor and attentional deficits in nigrostriatal 6-hydroxydopamine-lesioned rats. Subjects were trained to depress a lever, detect a stimulus occurring after variable foreperiods, and release the lever quickly afterward. Striatal DA depletions produce deficits in the timing of foreperiods and prolong reaction times. Although a subchronic treatment with piribedil (0.1-2 mg/kg) is not effective, a dose of 0.3 mg/kg administered for 3 weeks significantly reverses the akinetic deficits produced by the striatal dopamine depletion and progressively improves attentional deficits. When coadministered with the dopamine prodrug l-3,4-dihydroxyphenylalanine (l-DOPA) (3 mg/kg), piribedil (0.3 mg/kg) promotes a rapid and full recovery of preoperative performance. These results suggest that administration of l-DOPA in combination with piribedil in a chronic treatment as either initial or supplemental therapy for Parkinson's disease might improve cognitive functions while reducing the risk for motor complications.

Animals↗

PubMed2005

Reward-related neuronal activity in the subthalamic nucleus of the monkey.

The subthalamic nucleus is a key structure for motor information processing in the basal ganglia. Little is known about its involvement in other aspects of behavior such as motivation. We investigated neuronal activity in the subthalamic nucleus while a monkey performed arm-reaching movements to obtain a liquid reward. Most neurons were modulated both during the movement and reward phases of the task. The changes in activity occurring after or just before the delivery of reward consisted of either increases or decreases in firing and were not directly related to mouth movements. These findings indicate that STN neurons are involved in the detection and expectation of reward, consistent with a role for these neurons in the processing of motivational information.

Action Potentials↗

PubMed2005

The subthalamic nucleus exerts opposite control on cocaine and 'natural' rewards.

A challenge in treating drug addicts is preventing their pathological motivation for the drug without impairing their general affective state toward natural reinforcers. Here we have shown that discrete lesions of the subthalamic nucleus greatly decreased the motivation of rats for cocaine while increasing it for food reward. The subthalamic nucleus, a key structure controlling basal ganglia outputs, is therefore able to oppositely modulate the effect of 'natural' rewards and drugs of abuse on behavior. Modulating the activity of the subthalamic nucleus might prove to be a new target for the treatment of cocaine addiction.

Animals↗

PubMed2005

Functional interaction between mGlu 5 and NMDA receptors in a rat model of Parkinson's disease.

RATIONALE: Electrophysiological evidence suggests a synergistic relationship between metabotropic (mGlu) and ionotropic (iGlu) glutamate receptors. The functional consequences of these interactions have not been investigated in neurodegenerative diseases such as in Parkinson's disease. OBJECTIVE: The goals of this study are as follows: (1) to investigate the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and dizocilpine (MK-801), antagonists at metabotropic glutamate 5 (mGlu5) and NMDA receptors, respectively, on the akinetic syndrome observed in bilateral 6-OHDA-lesioned rats; (2) to investigate if the effects of MPEP were potentiated by co-treatment with a behaviorally inactive dose of MK-801; and (3) to investigate the effects of L-DOPA alone and in combination with MPEP on the akinetic syndrome observed in 6-OHDA-lesioned rats. METHODS: The effects of the different treatments (single and co-treatment) administered for 3 weeks were measured in 6-OHDA-lesioned rats trained to release a lever rapidly after a visual stimulus onset in a simple reaction time task. RESULTS: MPEP 0.75 mg/kg reversed the akinetic deficits produced by striatal dopamine depletion, while MPEP 0.375 mg/kg had no effect. Co-administration with MK-801 0.02 mg/kg, ineffective alone, failed to speed the recovery process of MPEP 0.75 mg/kg but revealed the anti-akinetic action of MPEP 0.375 mg/kg. L-DOPA 3 mg/kg alone had a potent anti-akinetic effect in 6-OHDA lesioned rats, and this effect was not potentiated by a subthreshold MPEP treatment. CONCLUSION: These results support a critical role for mGlu5 receptor blockade in improving parkinsonian symptomatology either as a single treatment or in combination with low concentrations of L-DOPA and demonstrate an interaction between NMDA and mGluR5 in regulating these effects.

Animals↗

PubMed2005

Addiction in Parkinson's disease: impact of subthalamic nucleus deep brain stimulation.

In Parkinson's disease, dopamine dysregulation syndrome (DDS) is characterized by severe dopamine addiction and behavioral disorders such as manic psychosis, hypersexuality, pathological gambling, and mood swings. Here, we describe the case of 2 young parkinsonian patients suffering from disabling motor fluctuations and dyskinesia associated with severe DDS. In addition to alleviating the motor disability in both patients, subthalamic nucleus (STN) deep brain stimulation greatly reduced the behavioral disorders as well as completely abolished the addiction to dopaminergic treatment. Dopaminergic addiction in patients with Parkinson's disease, therefore, does not constitute an obstacle to high-frequency STN stimulation, and this treatment may even cure the addiction.

Adult↗

PubMed2005

Lesions to the subthalamic nucleus decrease impulsive choice but impair autoshaping in rats: the importance of the basal ganglia in Pavlovian conditioning and impulse control.

Although the subthalamic nucleus (STN) is involved in regulating motor function, and inactivation of this structure relieves the motor symptoms in Parkinsonian patients, recent data indicate that corticosubthalamic connections are involved in both the regulation of attention and the ability to withhold from responding. Considerable evidence suggests that the neural circuitry underlying such behavioural disinhibition or impulsive action can be at least partially dissociated from that implicated in impulsive decision-making and it has been suggested that the tendency to choose impulsively is related to the ability to form and use Pavlovian associations. To explore these hypotheses further, STN-lesioned rats were tested on the delay-discounting model of impulsive choice, where impulsivity is defined as the selection of a small immediate over a larger delayed reward, as well as in a rodent autoshaping paradigm. In contrast to previous reports of increased impulsive action, STN lesions decreased impulsive choice but dramatically impaired the acquisition of the autoshaping response. When the STN was lesioned after the establishment of autoshaping behaviour, lesioned subjects were more sensitive to the omission of reward, indicative of a reduction in the use of Pavlovian associations to control autoshaping performance. These results emphasize the importance of the STN in permitting conditioned stimulus-unconditioned stimulus associations to regulate goal-seeking, a function which may relate to the alterations in impulsive choice observed in the delay-discounting task. These data bear a striking similarity to those observed after lesions of the orbitofrontal cortex and are suggestive of an important role for corticosubthalamic connections in complex cognitive behaviour.

Animals↗

PubMed2004

Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation-induced cellular defects in the rat striatum and globus pallidus.

This study examined the effects of prolonged (4 days) high frequency stimulation (HFS) of the subthalamic nucleus (STN), in comparison with those of STN lesion, on the dopamine denervation-mediated cellular changes in the basal ganglia in a Wistar rat model of Parkinson's disease. STN HFS counteracted the dopamine lesion-induced increase in GAD67 mRNA expression in the output structures of the basal ganglia, as shown previously after STN lesion, providing cellular support for the similar antiparkinsonian benefits produced by the two surgical procedures. The dopamine denervation-induced increase in GAD67 mRNA levels in the globus pallidus was partially antagonized after HFS and totally reversed after ibotenate-induced STN lesion. The overexpression of striatal enkephalin mRNA tended to be further increased by HFS but was antagonized by STN lesion. The decrease in striatal substance P mRNA levels was affected neither by STN HFS nor lesion. As STN HFS for two hours was previously found not to interfere with the effects of dopamine lesion in the globus pallidus and striatum, the present data provide strong evidence that the effects of STN surgery in these structures involve long-term adaptive processes and that the rearrangements mediated by HFS and lesion are, at least in part, different.

Animals↗

PubMed2003

Functional disconnection of the medial prefrontal cortex and subthalamic nucleus in attentional performance: evidence for corticosubthalamic interaction.

The present study used a disconnection procedure to test whether the medial prefrontal cortex (mPFC) and the subthalamic nucleus (STN) were functional components in a common neural system that controlled continuous performance in a test of sustained and divided visual attention. Animals with disconnected lesions of the mPFC and STN in contralateral hemispheres were severely impaired in several aspects of performance, including discriminative accuracy, increased perseveration, and slowed response latencies during postoperative testing. These deficits persisted throughout the entire experimental test period. Increasing the stimulus duration alleviated the accuracy deficit but failed to improve speed of responding or reduce perseverative responses. These deficits were in marked contrast to animals with combined mPFC and STN lesions made on the ipsilateral side, which produced behavior not different from that of sham controls. Rats with unilateral lesions of either structure alone were also impaired in terms of accuracy and perseveration. These data suggest that some of the deficits observed after bilateral STN lesions (attention and perseveration) may be attributable to a disrupted corticosubthalamic projection. This study provides direct evidence that performance in tasks that require optimal attentional and executive control relies on a corticosubthalamic interaction within the neural circuitry of the basal ganglia.

Animals↗

PubMed2003

High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task.

Chronic subthalamic nucleus high frequency stimulation (STN HFS) improves motor function in Parkinson's disease. However, its efficacy on cognitive function and the mechanisms involved are less known. The aim of this study was to assess the effects of STN HFS in hemiparkinsonian awake rats performing different specific motor tests and a cognitive operant task. Unilateral STN HFS applied in unilaterally DA-depleted rats decreased the apomorphine-induced circling behaviour and reduced catalepsy induced by the neuroleptic haloperidol. DA-depleted rats exhibited severe deficits in the operant task, among which the inability to perform the task was not alleviated by STN HFS. However, in a few animals showing less impairment, STN HFS significantly reduced the contralateral neglect induced by the lesion. These results are the first to demonstrate a beneficial effect of STN HFS applied in awake rats on basic motor functions. However, STN HFS appears to be less effective on impaired cognitive functions.

Adrenergic Agents↗

PubMed2002

Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism.

Metabotropic glutamate receptors (mGluRs) have recently been considered as potential pharmacological targets in the treatment of neurodegenerative disorders and particularly in parkinsonism. Within the basal ganglia, receptors of group I (mGluR1 and mGluR5) are widely expressed; the present study was thus aimed at blocking these receptors in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease in the rat. Considering the prominent expression of mGluR5, we have used the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) to target these receptors. In rats trained to quickly depress a lever after a visual cue, bilateral lesions of the dopaminergic nerve terminals in the striatum produced severe akinetic deficits, which were expressed by increases in delayed responses and reaction times. Acute MPEP injection (1.5, 3, and 6 mg/kg, i.p.) had no effect, whereas chronic administration, ineffective in a control group, significantly reversed the akinetic deficits. Alleviation of these deficits was seen after 1 week of treatment, and the preoperative performance was fully recovered after a 3 week treatment of MPEP at all doses. Chronic MPEP also induced ipsilateral rotation in the unilateral 6-OHDA circling model. However, no effect was seen of MPEP (1.5, 3, or 6 mg/kg, i.p.) on haloperidol-induced catalepsy (1 mg/kg, i.p.). Altogether, these results suggest a specific role of mGluRs in the regulation of extrapyramidal motor functions and a potential therapeutic value for mGluR5 antagonists in the treatment of Parkinson's disease.

Animals↗

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↗

PubMed2002

Cocaine and amphetamine depress striatal GABAergic synaptic transmission through D2 dopamine receptors.

The striatum is a brain area implicated in the pharmacological action of drugs of abuse. To test the possible involvement of both cocaine and amphetamine in the modulation of synaptic transmission in this nucleus, we coupled whole-cell patch clamp recordings from striatal spiny neurons to the focal stimulation of glutamatergic or GABAergic nerve terminals. We found that neither cocaine (1-600 microM) nor amphetamine (0.3-300 microM) significantly affected the glutamate-mediated EPSCs recorded from these cells. Conversely, both pharmacological agents depressed GABA-mediated IPSCs in a dose-dependent manner. This effect was mediated by the stimulation of dopamine (DA) D2 receptors since it was prevented by 3 microM L-sulpiride (a DA D2-like receptor antagonist), mimicked by the DA D2-like receptor agonist quinpirole (0.3-30 microM), and absent in mice lacking DA D2 receptors. A presynaptic mechanism was likely involved in this action since both cocaine and amphetamine depress GABAergic transmission by increasing paired-pulse facilitation. Cocaine and amphetamine failed to affect GABAergic IPSCs after 6-OHDA-induced nigral lesion, indicating that both drugs cause their effects through the release of endogenous DA. The modulation of GABAergic synaptic transmission in the striatum might underlie some motor and cognitive effects of psychostimulants in mammalians.

6-Cyano-7-nitroquinoxaline-2,3-dione↗