Behavioral recovery in MPTP-treated monkeys: neurochemical mechanisms studied by intrastriatal microdialysis.

Parkinson's disease (PD) patients express motor symptoms only after 60-80% striatal dopamine (DA) depletion. The presymptomatic phase of the disease may be sustained by biochemical modifications within the striatum. We used an appropriate specific 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model (Mounayar et al., 2007) to study the compensatory mechanisms operating in recovery from PD motor symptoms. We assessed the levels of DA and its metabolites (DOPAC, homovanillic acid), GABA, glutamate (Glu), serotonin (5-HT) and its metabolite (5HIAA) by repeated intracerebral microdialysis in awake animals before exposure to MPTP during full expression of the motor symptoms induced by MPTP and after recovery from these symptoms. Measurements were obtained from two functionally and anatomically different striatal areas: the associative-limbic territory and sensorimotor territory. Animals with motor symptoms displayed an extremely large decrease in levels of DA and its metabolites and an increase in Glu and GABA levels, as reported by other studies. However, we show here for the first time that serotonin levels increased in these animals. We found that increases in DA levels in the sensorimotor and/or associative-limbic territory and high levels of 5-HT and of its metabolite, 5HIAA, were associated with recovery from motor symptoms in this model. Determining whether similar changes in DA and 5-HT levels are involved in the compensatory mechanisms delaying the appearance of motor symptoms in the early stages of PD might make it possible to develop new treatment strategies for the disease.

Subthalamic stimulation-induced forelimb dyskinesias are linked to an increase in glutamate levels in the substantia nigra pars reticulata.

The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates the motor symptoms of Parkinson's disease (PD) remain unclear. In this study, we analyzed the effects of STN-HFS on motor behavior in intact or hemiparkinsonian rats (6-hydroxydopamine lesion of the substantia nigra pars compacta) and investigated the correlation between these effects and extracellular glutamate (Glu) and GABA levels, assessed by intracerebral microdialysis in the substantia nigra pars reticulata (SNr). STN-HFS at an intensity corresponding to the threshold inducing contralateral forelimb dyskinesia, increased Glu levels in the SNr of both intact and hemiparkinsonian rats. In contrast, STN-HFS at half this intensity did not affect Glu levels in the SNr in intact or hemiparkinsonian rats but increased GABA levels in hemiparkinsonian rats only. STN-HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr. These new neurochemical data suggest that STN-HFS-induced forelimb dyskinesia is mediated by glutamate, probably via the direct activation of STN axons, shedding light on the mechanisms of STN-HFS in PD.

Which memory processes are affected in patients with obstructive sleep apnea? An evaluation of 3 types of memory.

STUDY OBJECTIVE: To investigate which memory processes are affected by obstructive sleep apnea (OSA). DESIGN: Three separate memory systems were investigated in patients with OSA and normal subjects. Verbal episodic memory was tested after forced encoding, in order to control the level of attention during item presentation; procedural memory was tested using a simplified version of a standard test with an interfering task; lastly, working memory was examined with validated paradigms based on a theoretical model. SETTING: Sleep laboratory and outpatient sleep clinic in a French tertiary-care university hospital. PARTICIPANTS: Ninety-five patients with OSA and 95 control subjects matched for age and level of education. Group 1 (54 patients, 54 controls) underwent an extensive battery of tasks evaluating verbal episodic, procedural, and working memory. Group 2 (16 patients, 16 controls) underwent procedural memory tests only, and group 3 (25 patients, 25 controls) working memory tests only. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Compared with matched controls, patients with OSA exhibited a retrieval deficit of episodic memory but intact maintenance, recognition, and forgetfulness; decreased overall performance in procedural memory, although pattern learning did occur; and impairment of specific working memory capabilities despite normal short-term memory. No consistent correlation was found between OSA severity and memory deficit. The long duration of the test session did not negatively impact the patients' performance. CONCLUSIONS: Memory impairment in OSA is mild and does not affect all memory processes but, rather, specific aspects, underscoring the need for extensive and specific memory testing in clinical and research settings.

Neurochemical mechanisms induced by high frequency stimulation of the subthalamic nucleus: increase of extracellular striatal glutamate and GABA in normal and hemiparkinsonian rats.

High frequency stimulation (HFS) (130 Hz) of the subthalamic nucleus (STN) provides beneficial effects in patients suffering from severe parkinsonism, but the mechanisms underlying these clinical results remain to be clarified. To date, very little is known concerning the effects of STN-HFS on neurochemical transmission in the different basal ganglia nuclei and in particular the striatum. This study examines the effects of STN-HFS in intact and hemiparkinsonian rats on extracellular striatal glutamate (Glu) and GABA levels by means of intracerebral microdialysis. Unilateral STN-HFS was found to induce a significant bilateral increase of striatal Glu and GABA both in intact and in dopamine-lesioned animals. In intact rats, these increases were reversed by local administration of the D1 antagonist SCH 23390, but were potentiated by the D2 antagonist sulpiride. Potentiation was also observed after local administration of both D1 and D2 antagonists whose amplitude was similar to that measured in hemiparkinsonian rats. These data furnish the first evidence that STN-HFS influences striatal amino-acid transmission and that this influence is modulated by dopamine. They provide evidence that the effects of STN-HFS are not only restricted to the direct STN targets, but also involve adaptive changes within other structures of the basal ganglia circuitry.

High-frequency stimulation of the subthalamic nucleus prolongs the increase in striatal dopamine induced by acute l-3,4-dihydroxyphenylalanine in dopaminergic denervated rats.

High-frequency stimulation of the subthalamic nucleus (STN-HFS) is a powerful approach for treating the motor symptoms of Parkinson's disease (PD). It results in clinical improvement in patients with PD, further reducing the l-3,4-dihydroxyphenylalanine (L-DOPA) requirement and thus L-DOPA-induced dyskinesia. However, it remains unclear how STN-HFS modifies the response to L-DOPA. We investigated the effect of STN-HFS on striatal extracellular concentrations of dopamine and its metabolites following acute L-DOPA administration in intact or partially dopaminergic denervated (DA-PL) rats. L-DOPA treatment significantly increased striatal dopamine levels in intact and DA-PL animals, with the maximal effect observed 1 h after L-DOPA injection. This increase was more pronounced in DA-PL rats (ipsilateral to the lesion) than in intact animals. It remained fairly stable 1 h after the maximal effect of L-DOPA and then decreased towards basal values. STN-HFS in intact rats had no effect on the maximal L-DOPA-induced increase in striatal extracellular dopamine concentration or the return to basal values, the profiles observed being similar to those for non-stimulated intact animals. Conversely, STN-HFS amplified the L-DOPA-induced increase in striatal dopamine levels during the stimulation period (1 h) in DA-PL rats and this increase was sustained throughout the post-stimulation period (2.5 h), without the return to basal levels observed in stimulated intact and non-stimulated rats. These new neurochemical data suggest that STN-HFS interferes with L-DOPA effects, probably synergically, by stabilizing dopamine levels in the striatum and shed light on the mechanisms of STN-HFS in PD.

Functional reinnervation from remaining DA terminals induced by GDNF lentivirus in a rat model of early Parkinson's disease.

Glial cell-line derived neurotrophic factor (GDNF) is a good candidate agent for restoring functional reinnervation and/or neuroprotection of dopamine (DA) nigrostriatal system and thus for the treatment of Parkinson's disease (PD). Viral delivery is currently the most likely in vivo strategy for delivery of the therapeutic protein into the brain for treatment of neurological diseases. However, one of the important unresolved issues for this strategy is the threshold number of DA nigral neurons and/or of striatal DA terminals necessary for optimal benefit from GDNF therapy. In this study, we examined the intrastriatal neurotrophic effects of long-term GDNF delivery using a lentiviral vector in a new rat model of early PD. Lenti-GDNF was injected into the striatum 4 weeks after partial substantia nigra pars compacta 6-hydroxydopamine-induced lesion. Striatal denervation was evaluated by assessing tyrosine hydroxylase-positive DA fiber density and corroborated by testing motor deficit by means of a staircase test. GDNF treatment restored complete striatal DA innervation in the previously denervated area and this was associated with significant behavioral improvements.

Influence of the frequency parameter on extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treatment for alleviating motor symptoms in Parkinson's disease (PD). However, the mechanisms of HFS underlying these clinical effects remain unknown. Using intracerebral microdialysis, we previously reported that HFS induces, in normal rats, a significant increase of extracellular glutamate (Glu) in the globus pallidus (GP in rats or GPe in primates) and the substantia nigra pars reticulata (SNr), whereas gamma-aminobutyric acid (GABA) was increased only in the SNr. Bradykinesia can be improved by STN stimulation in a frequency-dependent manner, a plateau being reached around 130 Hz. The aim of the present study was to determine whether neurochemical changes are also frequency dependent. Electrical STN stimulation was applied at various frequencies (10, 60, 130, and 350 Hz) in normal rats. The results show that, for Glu, the amplitude of increase detected in GP and SNr is maximal at 130 Hz and is maintained at 350 Hz. No modifications of GABA were observed in GP whatever the frequency applied, whereas, in SNr, GABA increased from 60 to 350 Hz. Our results provide new neurochemical data implicating STN target structures in deep-brain-stimulation mechanisms.