Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks.

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modeling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use.

The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes, dopamine (DA), is suspected to play an important role in this pathology, but its exact role remains to be determined. Here, we found that rats expressing compulsive-like alcohol use, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that chemogenetic-induced selective hypodopaminergia of this pathway resulted in compulsive-like alcohol self-administration in otherwise resilient rats, accompanied by the emergence of alcohol withdrawal-like motivational impairments (i.e., impaired motivation for a natural reinforcer). Finally, the use of the monoamine stabilizer OSU6162, previously reported to correct hypodopaminergic states, transiently decreased compulsive-like alcohol self-administration in vulnerable rats. These results suggest a potential critical role of tonic nigrostriatal hypodopaminergic states in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

Dopamine D3 Receptors: A Potential Target to Treat Motivational Deficits in Parkinson's Disease.

Parkinson's disease (PD), which is traditionally viewed as a motor disorder involving the degeneration of dopaminergic (DA) neurons, has recently been identified as a quintessential neuropsychiatric condition. Indeed, a plethora of non-motor symptoms may occur in PD, including apathy. Apathy can be defined as a lack of motivation or a deficit of goal-directed behaviors and results in a pathological decrease of self-initiated voluntary behavior. Apathy in PD appears to fluctuate with the DA state of the patients, suggesting a critical role of DA neurotransmission in the pathophysiology of this neuropsychiatric syndrome. Using a lesion-based approach, we developed a rodent model which exhibits specific alteration in the preparatory component of motivational processes, reminiscent to apathy in PD. We found a selective decrease of DA D3 receptors (D3R) expression in the dorsal striatum of lesioned rats. Next, we showed that inhibition of D3R neurotransmission in non-lesioned animals was sufficient to reproduce the motivational deficit observed in our model. Interestingly, we also found that pharmacologically targeting D3R efficiently reversed the motivational deficit induced by the lesion. Our findings, among other recent data, suggest a critical role of D3R in parkinsonian apathy and highlight this receptor as a promising target for treating motivational deficits.

A metabolic biomarker predicts Parkinson's disease at the early stages in patients and animal models.

BackgroundCare management of Parkinson's disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detection of PD therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in 3 different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, nonmotor signs and, very interestingly, also discriminated PD patients from healthy subjects.ConclusionFrom our translational study, which included 3 animal models and 3 de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis that may possibly predict early PD development, before motor symptoms appear.FundingFrench National Research Agency (ANR), DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Association France Parkinson.

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a technical revolution in integrative neuroscience. However, the first used ligands exhibited dose-dependent selectivity for their molecular target, leading to potential unspecific effects. Compound 21 (C21) was recently proposed as an alternative, but in vivo characterization of its properties is not sufficient yet. Here, we evaluated its potency to selectively modulate the activity of nigral dopaminergic (DA) neurons through the canonical DREADD receptor hM4Di using TH-Cre rats. In males, 1 mg.kg-1 of C21 strongly increased nigral neurons activity in control animals, indicative of a significant off-target effect. Reducing the dose to 0.5 mg.kg-1 circumvented this unspecific effect, while activated the inhibitory DREADDs and selectively reduced nigral neurons firing. In females, 0.5 mg.kg-1 of C21 induced a transient and residual off-target effect that may mitigated the inhibitory DREADDs-mediated effect. This study raises up the necessity to test selectivity and efficacy of chosen ligands for each new experimental condition.

Subthalamic Nucleus Stimulation Impairs Motivation: Implication for Apathy in Parkinson's Disease.

BACKGROUND: Apathy is one of the most disabling neuropsychiatric symptoms in Parkinson's disease (PD) patients and has a higher prevalence in patients under subthalamic nucleus deep brain stimulation. Indeed, despite its effectiveness for alleviating PD motor symptoms, its neuropsychiatric repercussions have not yet been fully uncovered. Because it can be alleviated by dopaminergic therapies, especially D2 and D3 dopaminergic receptor agonists, the commonest explanation proposed for apathy after subthalamic nucleus deep brain stimulation is a too-strong reduction in dopaminergic treatments. The objective of this study was to determine whether subthalamic nucleus deep brain stimulation can induce apathetic behaviors, which remains an important matter of concern. We aimed to unambiguously address this question of the motivational effects of chronic subthalamic nucleus deep brain stimulation. METHODS: We longitudinally assessed the motivational effects of chronic subthalamic nucleus deep brain stimulation by using innovative wireless microstimulators, allowing continuous stimulation of the subthalamic nucleus in freely moving rats and a pharmacological therapeutic approach. RESULTS: We showed for the first time that subthalamic nucleus deep brain stimulation induces a motivational deficit in naive rats and intensifies those existing in a rodent model of PD neuropsychiatric symptoms. As reported from clinical studies, this loss of motivation was fully reversed by chronic treatment with pramipexole, a D2 and D3 dopaminergic receptor agonist. CONCLUSIONS: Taken together, these data provide experimental evidence that chronic subthalamic nucleus deep brain stimulation by itself can induce loss of motivation, reminiscent of apathy, independently of the dopaminergic neurodegenerative process or reduction in dopamine replacement therapy, presumably reflecting a dopaminergic-driven deficit. Therefore, our data help to clarify and reconcile conflicting clinical observations by highlighting some of the mechanisms of the neuropsychiatric side effects induced by chronic subthalamic nucleus deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.

Mapping Chemical Elements and Iron Oxidation States in the Substantia Nigra of 6-Hydroxydopamine Lesioned Rats Using Correlative Immunohistochemistry With Proton and Synchrotron Micro-Analysis.

Brain metal homeostasis is altered in neurodegenerative diseases and the concentration, the localization and/or the chemical speciation of the elements can be modified compared to healthy individuals. These changes are often specific to the brain region affected by the neurodegenerative process. For example, iron concentration is increased in the substantia nigra (SN) of Parkinson's disease patients and iron redox reactions might be involved in the pathogenesis. The identification of the molecular basis behind metal dyshomeostasis in specific brain regions is the subject of intensive research and chemical element imaging methods are particularly useful to address this issue. Among the imaging modalities available, Synchrotron X-ray fluorescence (SXRF) and particle induced X-ray emission (PIXE) using focused micro-beams can inform about the quantitative distribution of metals in specific brain regions. Micro-X-ray absorption near edge spectroscopy (XANES) can in addition identify the chemical species of the elements, in particular their oxidation state. However, in order to bring accurate information about metal changes in specific brain areas, these chemical imaging methods must be correlated to brain tissue histology. We present a methodology to perform chemical element quantitative mapping and speciation on well-identified brain regions using correlative immunohistochemistry. We applied this methodology to the study of an animal model of Parkinson's disease, the 6-hydroxydopamine (6-OHDA) lesioned rat. Tyrosine hydroxylase immunohistochemical staining enabled to identify the SN pars compacta (SNpc) and pars reticulata (SNpr) as well as the ventral tegmental area (VTA). Using PIXE we found that iron content was higher respectively in the SNpr > SNpc > VTA, but was not statistically significantly modified by 6-OHDA treatment. In addition, micro-SXRF revealed the higher manganese content in the SNpc compared to the SNpr. Using micro-XANES we identified Fe oxidation states in the SNpr and SNpc showing a spectral similarity comparable to ferritin for all brain regions and exposure conditions. This study illustrates the capability to correlate immunohistochemistry and chemical element imaging at the brain region level and this protocol can now be widely applied to other studies of metal dyshomeostasis in neurology.

GLS1 Mutant Mice Display Moderate Alterations of Hippocampal Glutamatergic Neurotransmission Associated with Specific Adaptive Behavioral Changes.

Significant alterations in glutamatergic neurotransmission have been reported in major depressive disorder (MDD) that could underlie psychiatric traits. Studies were mainly interested in synaptic dysfunction in the prefrontal cortex, a key structure involved in depressive-like behavior, however hippocampus has been shown to be important in MDD. As cognitive deficits such as hippocampus-memory process were observed in MDD, we investigated in a mild hypoglutamatergic model behaviors related to depression and memory, synaptic transmission parameters and glutamatergic state specifically in the hippocampus. We thus characterized these phenotypes in adult male mice partially depleted in glutaminase type 1 or GLS1 (GLS1 HET), the enzyme responsible for glutamate synthesis in neurons, that we previously characterized as displaying moderate lower levels of glutamate in brain. We showed that GLS1 mutant mice display AMPA-R-mediated response deficits after prolonged repetitive stimulation with electrophysiological recording and inability to sustain glutamate release by microdialysis experiments with no consequences on behavioral spatial learning performances. However, their ability to escape from unpleasant but repeated escapable condition was attenuated whereas they were more immobile in the unescapable situation in the FST during re-test. These results show that GLS1 mutant mice display moderate impairments of hippocampal glutamatergic neurotransmission and moderate changes in adaptive behaviors that have been shown to participate to the development of depressive-like state.

Plasma or serum? A qualitative study on rodents and humans using high-throughput microRNA sequencing for circulating biomarkers.

microRNAs are small non-coding RNAs gaining interest for their potential roles as reliable biomarkers for the diagnosis and therapeutics of numerous pathologies, ranging from cancer to neurodegenerative or psychiatric disorders. Indeed, microRNAs are present in various accessible biofluids, including peripheral blood, and specific dysregulation of their expression may be associated with these different pathological conditions. microRNAs can be isolated from plasma or serum for sequencing with commercial kits. However, these two biofluids might exhibit some differences in their microRNA contents, due notably to the coagulation process occurring during serum collection. It remains unclear from previous studies and commercial recommendations which blood fraction is preferable. Because of the small amount of circulating microRNAs in a given blood volume, this question appears crucial for qualitative and quantitative optimization of microRNA profiling, especially in animal models used for investigating the pathophysiological relevancy of this approach. We therefore evaluated the efficiency of RNA isolation and microRNA levels from plasma and sera isolated from rats and humans, with a widely used extraction kit (QIAGEN miRNeasy), and assessed microRNA quality and quantity with high-throughput sequencing. Fewer reads with length corresponding to non-miRNAs sequences were observed in plasma than in serum, both from rats and humans. Moreover, rat plasma produced twice as many aligned reads compared to sera, as well as more aligned reads corresponding to microRNAs (84.6% against 38.7%), differences that were not find in human samples. Our results, therefore, clearly indicate that plasma should be preferred for miRNA investigations, particularly for translational studies.

Nigrostriatal Dopaminergic Denervation Does Not Promote Impulsive Choice in the Rat: Implication for Impulse Control Disorders in Parkinson's Disease.

Impulse control disorders (ICDs) are frequent behavioral complications of dopaminergic (DA) replacement therapies (DRTs) in Parkinson's disease (PD). Impulsive choice, which refers to an inability to tolerate delays to reinforcement, has been identified as a core pathophysiological process of ICDs. Although impulsive choices are exacerbated in PD patients with ICDs under DRTs, some clinical and preclinical studies suggest that the DA denervation of the dorsal striatum induced by the neurodegenerative process as well as a pre-existing high impulsivity trait, may both contribute to the emergence of ICDs in PD. We therefore investigated in a preclinical model in rats, specifically designed to study PD-related non-motor symptoms, the effect of nigrostriatal DA denervation on impulsive choice, in relation to pre-existing levels of impulsivity, measured in a Delay Discounting Task (DDT). In this procedure, rats had the choice between responding for a small sucrose reinforcer delivered immediately, or a larger sucrose reinforcer, delivered after a 0, 5, 10 or 15 s delay. In two different versions of the task, the preference for the large reinforcer decreased as the delay increased. However, and in contrast to our initial hypothesis, this discounting effect was neither exacerbated by, or related to, the extent of the substantia nigra pars compacta (SNc) DA lesion, nor it was influenced by pre-existing variability in impulsive choice. These results therefore question the potential implication of the nigrostriatal DA system in impulsive choice, as well as the DA neurodegenerative process as a factor contributing significantly to the development of ICDs in PD.

Organization of the Anterior Limb of the Internal Capsule in the Rat.

Dysfunction of the orbitofrontal (OFC) and anterior cingulate (ACC) cortices has been linked with several psychiatric disorders, including obsessive-compulsive disorder, major depressive disorder, posttraumatic stress disorder, and addiction. These conditions are also associated with abnormalities in the anterior limb of the internal capsule, the white matter (WM) bundle carrying ascending and descending fibers from the OFC and ACC. Furthermore, deep-brain stimulation (DBS) for psychiatric disorders targets these fibers. Experiments in rats provide essential information on the mechanisms of normal and abnormal brain anatomy, including WM composition and perturbations. However, whereas descending prefrontal cortex (PFC) fibers in primates form a well defined and topographic anterior limb of the internal capsule, the specific locations and organization of these fibers in rats is unknown. We address this gap by analyzing descending fibers from injections of an anterograde tracer in the rat ACC and OFC. Our results show that the descending PFC fibers in the rat form WM fascicles embedded within the striatum. These bundles are arranged topographically and contain projections, not only to the striatum, but also to the thalamus and brainstem. They can therefore be viewed as the rat homolog of the primate anterior limb of the internal capsule. Furthermore, mapping these projections allows us to identify the fibers likely to be affected by experimental manipulations of the striatum and the anterior limb of the internal capsule. These results are therefore essential for translating abnormalities of human WM and effects of DBS to rodent models.SIGNIFICANCE STATEMENT Psychiatric diseases are linked to abnormalities in specific white matter (WM) pathways, and the efficacy of deep-brain stimulation relies upon activation of WM. Experiments in rodents are necessary for studying the mechanisms of brain function. However, the translation of results between primates and rodents is hindered by the fact that the organization of descending WM in rodents is poorly understood. This is especially relevant for the prefrontal cortex, abnormal connectivity of which is central to psychiatric disorders. We address this gap by studying the organization of descending rodent prefrontal pathways. These fibers course through a subcortical structure, the striatum, and share important organization principles with primate WM. These results allow us to model primate WM effectively in the rodent.

Implication of dorsostriatal D3 receptors in motivational processes: a potential target for neuropsychiatric symptoms in Parkinson's disease.

Beyond classical motor symptoms, motivational and affective deficits are frequently observed in Parkinson's disease (PD), dramatically impairing the quality of life of patients. Using bilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in rats, we have been able to reproduce these neuropsychiatric/non-motor impairments. The present study describes how bilateral 6-OHDA SNc lesions affect the function of the main striatal dopaminergic (DA) receptor subtypes. Autoradiography was used to measure the levels of striatal DA receptors, and operant sucrose self-administration and neuropharmacological approaches were combined to investigate the causal implication of specific DA receptors subtypes in the motivational deficits induced by a dorsostriatal DA denervation. We found that D3 receptors (D3R) exclusively are down-regulated within the dorsal striatum of lesioned rats. We next showed that infusion of a D3R antagonist (SB-277011A) in non-lesioned animals specifically disrupts preparatory, but not consummatory behaviors. Our findings reveal an unexpected involvement of dorsostriatal D3R in motivational processes. They strongly suggest an implication of dorsostriatal D3R in the neuropsychiatric symptoms observed in PD, highlighting this receptor as a potential target for pharmacological treatment.

Chronic Intermittent Hypoxia Induces Chronic Low-Grade Neuroinflammation in the Dorsal Hippocampus of Mice.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) induces cognitive impairment that involves intermittent hypoxia (IH). Because OSA is recognized as a low-grade systemic inflammatory disease and only some patients develop cognitive deficits, we investigated whether IH-related brain consequences shared similar pathophysiology and required additional factors such as systemic inflammation to develop. DESIGN: Nine-week-old male C57BL/6J mice were exposed to 1 day, 6 or 24 w of IH (alternating 21-5% FiO2 every 30 sec, 8 h/day) or normoxia. Microglial changes were assessed in the functionally distinct dorsal (dH) and ventral (vH) regions of the hippocampus using Iba1 immunolabeling. Then the study concerned dH, as vH only tended to be lately affected. Seven proinflammatory and anti-inflammatory cytokine messenger RNA (mRNA) were assessed at all time points using semiquantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Similar mRNA analysis was performed after 6 w IH or normoxia associated for the past 3 w with repeated intraperitoneal low-dose lipopolysaccharide or saline. MEASUREMENTS AND RESULTS: Chronic (6, 24 w) but not acute IH induced significant microglial changes in dH only, including increased density and morphological features of microglia priming. In dH, acute but not chronic IH increased IL-1ß and RANTES/CCL5 mRNA, whereas the other cytokines remained unchanged. In contrast, chronic IH plus lipopolysaccharide increased interleukin (IL)-6 and IL10 mRNA whereas lipopolysaccharide alone did not affect these cytokines. CONCLUSION: The obstructive sleep apnea component intermittent hypoxia (IH) causes low-grade neuroinflammation in the dorsal hippocampus of mice, including early but transient cytokine elevations, delayed but long-term microglial changes, and cytokine response alterations to lipopolysaccharide inflammatory challenge. These changes may contribute to IH-induced cognitive impairment and pathological brain aging.

Subthalamic deep brain stimulation differently alters striatal dopaminergic receptor levels in rats.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is recognized as an effective treatment for the motor symptoms of Parkinson's disease (PD), but its mechanisms, particularly as concern dopaminergic transmission, remain unclear. The aim of this study was to evaluate changes in the expression of dopaminergic receptors (D1, D2, and D3 receptors) after prolonged (4 h) unilateral STN-HFS in anesthetized intact rats and rats with total dopaminergic denervation. We used [(3)H]SCH 23390, [(125)I]iodosulpride, and [(125)I]OH-PIPAT to assess the densities of D1R, D2R, and D3R, respectively, within different areas of the striatum-a major input structure of the basal ganglia-including the nucleus accumbens. We found that STN-HFS increased D1 R levels in almost all of the striatal areas examined, in both intact and denervated rats. By contrast, STN-HFS led to a large decrease in D2 R and D3R levels, limited to the nucleus accumbens and independent of the dopaminergic state of the animals. These data suggest that the influence of STN-HFS on striatal D1 R expression may contribute to its therapeutic effects on motor symptoms, whereas its impact on D2R/D3 R levels in the nucleus accumbens may account for the neuropsychiatric side effects often observed in stimulated PD patients, such as postoperative apathy.

Pramipexole reverses Parkinson's disease-related motivational deficits in rats.

Recent evidence suggests that Parkinson's disease affects not only movement, but also cognitive and psychiatric functions. Among these nonmotor complications, apathy, which is defined as a lack of motivation and operationalized as a quantitative reduction in goal-directed behavior, may even precede motor impairments, disappearing with the introduction of dopaminergic (DA) therapies and possibly reappearing with its discontinuation, suggesting a causal role of DA. We recently developed a lesion-based model, with stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into precise areas of the rat SNc or ventral tegmental area and showed, in several operant tasks, that a partial denervation of the nigrostriatal, but not of the mesocorticolimbic, DA system induced profound motivational deficits during instrumental action. We investigated the time course of the effects of nigrostriatal DA denervation on motivation in rats, by assessing the negative effect of SNc bilateral 6-OHDA infusion on preacquired operant behavior, and determining whether the induced deficits were sensitive to the introduction and withdrawal of a clinically relevant PD treatment, the DA D2/D3 receptor agonist, pramipexole (PRA). Partial nigrostriatal DA denervation was accompanied by a significant reduction in operant behavior. This deficit, indicative of a decrease in motivation, was fully reversed by PRA and reappeared after treatment withdrawal. This longitudinal preclinical study provides evidence for the implication of the DA nigrostriatal system in PD-associated apathy. Moreover, by showing a good isomorphy and predictive value, our model highlights the relevance of D2/D3 receptors as potential targets for alleviating apathy in PD.

High-frequency stimulation of the subthalamic nucleus modifies the expression of vesicular glutamate transporters in basal ganglia in a rat model of Parkinson's disease.

BACKGROUND: It has been suggested that glutamatergic system hyperactivity may be related to the pathogenesis of Parkinson's disease (PD). Vesicular glutamate transporters (VGLUT1-3) import glutamate into synaptic vesicles and are key anatomical and functional markers of glutamatergic excitatory transmission. Both VGLUT1 and VGLUT2 have been identified as definitive markers of glutamatergic neurons, but VGLUT 3 is also expressed by non glutamatergic neurons. VGLUT1 and VGLUT2 are thought to be expressed in a complementary manner in the cortex and the thalamus (VL/VM), in glutamatergic neurons involved in different physiological functions. Chronic high-frequency stimulation (HFS) of the subthalamic nucleus (STN) is the neurosurgical therapy of choice for the management of motor deficits in patients with advanced PD. STN-HFS is highly effective, but its mechanisms of action remain unclear. This study examines the effect of STN-HFS on VGLUT1-3 expression in different brain nuclei involved in motor circuits, namely the basal ganglia (BG) network, in normal and 6-hydroxydopamine (6-OHDA) lesioned rats. RESULTS: Here we report that: 1) Dopamine(DA)-depletion did not affect VGLUT1 and VGLUT3 expression but significantly decreased that of VGLUT2 in almost all BG structures studied; 2) STN-HFS did not change VGLUT1-3 expression in the different brain areas of normal rats while, on the contrary, it systematically induced a significant increase of their expression in DA-depleted rats and 3) STN-HFS reversed the decrease in VGLUT2 expression induced by the DA-depletion. CONCLUSIONS: These results show for the first time a comparative analysis of changes of expression for the three VGLUTs induced by STN-HFS in the BG network of normal and hemiparkinsonian rats. They provide evidence for the involvement of VGLUT2 in the modulation of BG cicuits and in particular that of thalamostriatal and thalamocortical pathways suggesting their key role in its therapeutic effects for alleviating PD motor symptoms.

Does MPTP intoxication in mice induce metabolite changes in the nucleus accumbens? A ¹H nuclear MRS study.

Using in vivo ¹H NMR spectroscopy in a mouse model of Parkinson's disease, we previously showed that glutamate concentrations in the dorsal striatum were highest after dopamine denervation associated with an increase in gamma-aminobutyric acid (GABA) and (Gln) glutamine levels. The aim of this study was to determine whether the changes previously observed in the motor part of the striatum were reproduced in a ventral part of the striatum, the nucleus accumbens (NAc). This study was carried out on controls and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. In vivo spectra were acquired for a voxel (8 µL) in the dorsal striatum, and in the NAc (1.56 µL). NMR acquisitions were first performed 10 days after the last MPTP injection in a basal condition [after saline intraperitoneal (i.p.) injection] and then in the same animal the week after basal NMR acquisitions, after acute levodopa administration (200 mg kg⁻¹, i.p.). Immunohistochemistry was used to determine the levels of (Glu) glutamate, glutamine synthetase (GS) and glutamic acid decarboxylase (GAD) isoform 67 in these two structures. The Glu, Gln and GABA concentrations obtained in the basal state were higher in the NAc of MPTP-intoxicated mice which have the higher dopamine denervation in the ventral tegmental area (VTA) and in the dorsal striatum. Levodopa decreased the levels of these metabolites in MPTP-intoxicated mice to levels similar to those in controls. In parallel, immunohistochemical staining showed that glutamate, GS and GAD67 immunoreactivity increased in the dorsal striatum of MPTP-intoxicated mice and in the NAc for animals with a severe dopamine denervation in VTA. These findings strongly supported a hyperactivity of the glutamatergic cortico-striatal pathway and changes in glial activity when the dopaminergic denervation in the VTA and substantia nigra pars compacta (SNc) was severe.