Abnormal aggregates of alpha-synuclein (α-syn) are pathologic hallmarks of Parkinson's disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).1, 2 Early detection of abnormal brain α-syn accumulation by a specific positron emission tomography (PET) radiotracer would be a major advancement in pathological diagnosis. The main development challenge is the intracellular nature of α-syn aggregates, their strain diversity, colocalization with other proteins, and low abundance. Despite years of effort, no molecule has been able to demonstrate sufficient binding.3 Endo and his colleagues have recently developed and characterized the 18F-C05-05 radiotracer that binds to α-syn fibrils and opens up new research prospects.4 This brilliant result was first obtained by an in vitro step aimed at modifying the structure of PBB3, a Tau tracer able to detect α-syn,5 and identifying the C05-05 compound. This modification altered the backbone torsion angle, which played a critical role in ligand affinity. They have examined in a second step the effectiveness of the tracer in detecting α-syn deposits in vivo, a few months after the inoculation of α-syn fibrils in the striatum of mice and of marmosets. Tracer binding was increased in striatal and nigral regions, in association with the loss of nigral dopaminergic neurons. Finally, the authors tested the efficacy of this radioligand in detecting α-syn deposits using autoradiography on postmortem human brain tissue and also using PET imaging in vivo. Notably, the tracer bound specifically in the basal ganglia of MSA subjects, in the amygdala of DLB subjects, and in the substantia nigra of PD subjects, in perfect spatial correlation with the immunofluorescent detection of α-syn on adjacent brain sections. In vivo, the binding was significantly increased in the mesencephalic region in subjects with PD and DLB compared with healthy subjects, and a positive correlation was found between the mesencephalic binding and the MDS-UPDRS, Part III, score. In MSA patients with predominant parkinsonism, higher radioligand binding was found in the putamen and in the middle cerebellar peduncle in some patients with cerebellar ataxia. Overall, this study has made a major breakthrough in the in vivo detection of different α-synucleinopathies, but some limitations such as potential cross-reactivity with Tau, nonspecific binding, and detection of low α-syn concentration remain. For future clinical investigation, as C05-05 exhibits a 10-fold lower selectivity for α-synucleinopathies compared to Alzheimer's disease, it would be interesting to implement it with properties of the F0502B tracer, which exhibited higher α-syn selectivity in preclinical studies.6 S.H.: execution, analysis, writing. V.S.: design, analysis, writing, editing. We thank the France Parkinson Association. S.H. was awarded a thesis grant by the France Parkinson Association. V.S. is employed by the French National Institute for Health and Medical Research. V.S. had a contract with Springer Nature as associate editor for npj Parkinson's Disease. The authors declare no financial disclosure and no conflict of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Impulse control disorders (ICDs) are frequent and particularly distressing neuropsychiatric symptoms in patients with Parkinson's disease, which are related to impaired behavioural inhibition. Multiple PET imaging studies indicate that striatal dopaminergic abnormalities contribute to hyperdopaminergic functioning in Parkinson's disease patients with ICD (PDICD+) and to the dysregulation of the limbic fronto-striatal networks, which are critical for reward-related decision impulsivity. However, the serotonergic system is central to response inhibition and plays a critical role in neuropsychiatric symptoms in PD, but its role remains undetermined in PDICD. We hypothesized that PDICD+ patients exhibit serotonergic dysfunction within the cortico-striato-pallido-thalamic circuits involved in the inhibitory control of behaviour and decided to investigate the pre- and postsynaptic serotonergic innervation using two highly specific PET tracers for the serotonin transporter (SERT) using 11C-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (11C-DASB) and the 5-HT2A receptor using 18F-altanserin. In this prospective, case-control, double-tracer PET study, we recruited 15 PDICD+ patients, 15 PDICD- patients and 15 healthy controls, matched for age and sex, and compared the availability of 11C-DASB and 18F-altanserin using permutation-based analysis. PDICD+ patients had one (n = 9) or multiple ICDs (n = 6), consisting of hypersexuality (n = 8), compulsive eating (n = 6), compulsive shopping (n = 5) and pathological gambling (n = 4), and were characterized by greater choice impulsivity (impaired delay discounting for monetary rewards) and greater urgency with more severe depressive and anxious symptoms. We demonstrate that PDICD+ patients had greater 11C-DASB binding in the posterior putamen and pallidum in comparison to PDICD- patients, corresponding to relatively preserved presynaptic SERT availability within the subcortical sensorimotor network involved in response inhibition. In addition, cortical 18F-altanserin binding was greater in PDICD+ patients in the bilateral supplementary motor area, precentral gyrus and right dorsolateral prefrontal cortex, involving the sensorimotor and associative networks which regulate behavioural inhibition. Furthermore, we show that pre- and postsynaptic serotonergic dysfunction subserving action versus decision impulsivity in patients with Parkinson's disease specifically followed the distinctive functional organization of the sensorimotor and associative fronto-striatal networks. Altogether, we demonstrate that serotonergic dysfunction related to ICDs in Parkinson's disease specifically involve the sensorimotor and associative cortico-striato-pallido-thalamic circuits involved in inhibitory control. Thus, serotonergic dysfunction contributes to the mechanisms related to the vulnerability and development of ICDs in patients with Parkinson's disease, beyond the known dopaminergic abnormalities in the limbic fronto-striatal circuit.

Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4R alterations in movement disorders. We wondered whether striatal 5-HT4R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson's disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4R might offer a therapeutic target for dampening PD's symptoms.

The interest in new 5-HT₆ agents stems from their ability to modulate cognition processing, food motivation and anxiety-like behaviors. While these findings come primarily from rodent studies, no studies on primates have been published. Furthermore, our understanding of where and how they act in the brain remains limited. Although the striatum is involved in all of these processes and expresses the highest levels of 5-HT₆ receptors, few studies have focused on it. We thus hypothesized that 5-HT6 receptor blockade would influence food motivation and modulate behavioral expression in non-human primates through striatal 5-HT6 receptors. This study thus aimed to determine the effects of acute administration of the SB-258585 selective 5-HT6 receptor antagonist on the feeding motivation and behaviors of six male macaques. Additionally, we investigated potential 5-HT6 targets using PET imaging to measure 5-HT6 receptor occupancy throughout the brain and striatal subregions. We used a food-choice task paired with spontaneous behavioral observations, checking 5-HT6 receptor occupancy with the specific PET imaging [18F]2FNQ1P radioligand. We demonstrated, for the first time in non-human primates, that modulation of 5-HT6 transmission, most likely through the striatum (the putamen and caudate nucleus), significantly reduces food motivation while exhibiting variable, weaker effects on behavior. While these results are consistent with the literature showing a decrease in food intake in rodents and proposing that 5-HT6 receptor antagonists can be used in obesity treatment, they question the antagonists' anxiolytic potential.

In recent years, particular attention has been paid to the serotonin 4 receptor, which is well expressed in the brain, but also peripherally in various organs. The cerebral distribution of this receptor is well conserved across species, with high densities in the basal ganglia, where they are expressed by GABAergic neurons. The 5-HT4 receptor is also present in the cerebral cortex, hippocampus, and amygdala, where they are carried by glutamatergic or cholinergic neurons. Outside the central nervous system, the 5-HT4 receptor is notably expressed in the gastrointestinal tract. The wide distribution of the 5-HT4 receptor undoubtedly contributes to its involvement in a plethora of functions. In addition, the modulation of this receptor influences the release of serotonin, but also the release of other neurotransmitters such as acetylcholine and dopamine. This is a considerable asset, as the modulation of the 5-HT4 receptor can therefore play a direct or indirect beneficial role in various disorders. One of the main advantages of this receptor is that it mediates a much faster antidepressant and anxiolytic action than classical selective serotonin reuptake inhibitors. Another major benefit of the 5-HT4 receptor is that its activation enhances cognitive performance, probably via the release of acetylcholine. The expression of the 5-HT4 receptor is also altered in various eating disorders, and its activation by the 5-HT4 agonist negatively regulates food intake. Additionally, although the cerebral expression of this receptor is modified in certain movement-related disorders, it is still yet to be determined whether this receptor plays a key role in their pathophysiology. Finally, there is no longer any need to demonstrate the value of 5-HT4 receptor agonists in the pharmacological management of gastrointestinal disorders.

Parkinson's disease (PD) is characterized by cell loss in the substantia nigra and the presence of alpha-synuclein (α-syn)-containing neuronal Lewy bodies. While α-syn has received major interest in the pathogenesis of PD, the function of beta- and gamma-synucleins (β-syn and γ-syn, respectively) is not really known. Yet, these proteins are members of the same family and also concentrated in neuronal terminals. The current preclinical study investigated the expression levels of α-, β-, and γ-synucleins in brainstem regions involved in PD physiopathology. We analyzed synuclein expression in the substantia nigra, raphe nuclei, pedunculopontine nucleus, and locus coeruleus from control and parkinsonian (by MPTP) macaques. MPTP-intoxicated monkeys developed a more or less severe parkinsonian score and were sacrificed after a variable post-MPTP period ranging from 1 to 20 months. The expression of the three synucleins was increased in the substantia nigra after MPTP, and this increase correlates positively, although not very strongly, with cell loss and motor score and not with the time elapsed after intoxication. In the dorsal raphe nucleus, the expression of the three synucleins was also increased, but only α- and γ-Syn are linked to the motor score and associated cell loss. Finally, although no change in synuclein expression was demonstrated in the locus coeruleus after MPTP, we found increased expression levels of γ-Syn, which are only correlated with cell loss in the pedunculopontine nucleus. Altogether, our data suggest that these proteins may play a key role in brainstem regions and mesencephalic tegmentum. Given the involvement of these brain regions in non-motor symptoms of PD, these data also strengthen the relevance of the MPTP macaque model of PD, which exhibits pathological changes beyond nigral DA cell loss and α-synucleinopathy.

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn) expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with: (i) γ-Syn overexpression induced by an adeno-associated viral vector and (ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, in order to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA release/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on substantia nigra pars compacta /ventral tegmental area (SNc/VTA) γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.

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.

Numerous clinical studies have shown that the serotonergic system also degenerates in patients with Parkinson's disease. The causal role of this impairment in Parkinson's symptomatology and the response to treatment remains to be refined, in particular thanks to approaches allowing the two components DA and 5-HT to be isolated if possible. We have developed a macaque monkey model of Parkinson's disease exhibiting a double lesion (dopaminergic and serotonergic) thanks to the sequential use of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MDMA (3,4-methylenedioxy-N-methamphetamine) (or MDMA prior MPTP). We characterized this monkey model by multimodal imaging (PET, positron emission tomography with several radiotracers; DTI, diffusion tensor imaging), behavioral assessments (parkinsonism, dyskinesia, neuropsychiatric-like behavior) and post-mortem analysis (with DA and 5-HT markers). When administrated after MPTP, MDMA damaged the 5-HT presynaptic system without affecting the remaining DA neurons. The lesion of 5-HT fibers induced by MDMA altered rigidity and prevented dyskinesia and neuropsychiatric-like symptoms induced by levodopa therapy in MPTP-treated animals. Interestingly also, prior MDMA administration aggravates the parkinsonian deficits and associated DA injury. Dystonic postures, action tremor and global spontaneous activities were significantly affected. All together, these data clearly indicate that late or early lesions of the 5-HT system have a differential impact on parkinsonian symptoms in the macaque model of Parkinson's disease. Whether MDMA has an impact on neuropsychiatric-like symptoms such as apathy, anxiety, depression remains to be addressed. Despite its limitations, this toxin-based double-lesioned monkey model takes on its full meaning and provides material for the experimental study of the heterogeneity of patients.

BACKGROUND:Parkinson's disease (PD) is characterized by heterogeneous motor and nonmotor manifestations related to alterations in monoaminergic neurotransmission systems. Nevertheless, the characterization of concomitant dopaminergic and serotonergic dysfunction after different durations of Parkinson's disease, as well as their respective involvement in the expression and severity of neuropsychiatric signs, has gained little attention so far. METHODS:To fill this gap, we conducted a cross-sectional study combining clinical and dual-tracer positron emission tomography (PET) neuroimaging approaches, using radioligands of dopamine ([11 C]-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane) ([11 C]PE2I) and serotonin ([11 C]-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine) ([11 C]DASB) reuptake, after different durations of Parkinson's disease (ie, in short-disease duration drug-naive de novo (n = 27, 0-2 years-duration), suffering from apathy (n = 14) or not (n = 13); intermediate-disease duration (n = 15, 4-7 years-duration) and long-disease duration, non-demented (n = 15, 8-10 years-duration) patients). Fifteen age-matched healthy subjects were also enrolled. RESULTS:The main findings are threefold: (1) both dopaminergic and serotonergic lesions worsen with the duration of Parkinson's disease, spreading from midbrain/subcortical to cortical regions; (2) the presence of apathy at PD onset is associated with more severe cortical and subcortical serotonergic and dopaminergic disruption, similar to the denervation pattern observed in intermediate-disease duration patients; and (3) the severity of parkinsonian apathy, depression, and trait-anxiety appears primarily related to serotonergic alteration within corticostriatal limbic areas. CONCLUSIONS:Altogether, these findings highlight the prominent role of serotonergic degeneration in the expression of several neuropsychiatric symptoms occurring after different durations of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

Background Care management of Parkinson’s disease (PD) patients currently remains symptomatic, especially because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Detecting PD earlier therefore represents a key step for developing therapies able to delay or slow down its progression. Methods We investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 2 cohorts of de novo PD patients (n = 95). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics. Results Our 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, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects. Conclusion From our translational study which included three animal models and two PD patient cohorts, we propose a promising composite biomarker exhibiting a high level of predictivity for PD diagnosis in its early phase, before motor symptoms appearance. Fundings ANR, DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Grenoble Alpes University.

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.

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat psychiatric disorders with affective biases such as depression and anxiety. How SSRIs exert a beneficial action on emotions associated with life events is still unknown. Here we ask whether and how the effectiveness of the SSRI fluoxetine is underpinned by neural mechanisms in the ventral striatum. To address these issues, we studied the spiking activity of neurons in the ventral striatum of monkeys during an approach-avoidance task in which the valence assigned to sensory stimuli was manipulated. Neural responses to positive and negative events were measured before and during a 4-week treatment with fluoxetine. We conducted PET scans to confirm that fluoxetine binds within the ventral striatum at a therapeutic dose. In our monkeys, fluoxetine facilitated approach of rewards and avoidance of punishments. These beneficial effects were associated with changes in tonic and phasic activities of striatal neurons. Fluoxetine increased the spontaneous firing rate of striatal neurons and amplified the number of cells responding to rewards versus punishments, reflecting a drug-induced positive shift in the processing of emotionally valenced information. These findings reveal how SSRI treatment affects ventral striatum neurons encoding positive and negative valence and striatal signaling of emotional information. In addition to a key role in appetitive processing, our results shed light on the involvement of the ventral striatum in aversive processing. Together, the ventral striatum appears to play a central role in the action of SSRIs on emotion processing biases commonly observed in psychiatric disorders.

Besides the hallmark motor symptoms (rest tremor, hypokinesia, rigidity, and postural instability), patients with Parkinson's disease (PD) have non-motor symptoms, namely neuropsychiatric disorders. They are frequent and may influence the other symptoms of the disease. They have also a negative impact on the quality of life of patients and their caregivers. In this article, we will describe the clinical manifestations of the main PD-related behavioral disorders (depression, anxiety disorders, apathy, psychosis, and impulse control disorders). We will also provide an overview of the clinical and preclinical literature regarding the underlying mechanisms with a focus on the role of the dopaminergic and non-dopaminergic systems.

EDITORIAL article Front. Pharmacol., 11 September 2020Sec. Neuropharmacology Volume 11 - 2020 | https://doi.org/10.3389/fphar.2020.593822

Parkinson's disease (PD) is a neurodegenerative disease characterized by classic motor signs but also non-motor signs that may precede the diagnosis. Braak and colleagues1 analyzed the topographical progression of Lewy bodies, which are histopathological markers of degeneration, on post-mortem tissue and hypothesized that the disease may start in the gastrointestinal tract and spread to the brain through the vagus nerve. Even if this hypothesis has been supported in the literature, several questions still exist about this topographical progression. In the study conducted by Arotcarena and colleagues,2 the authors wanted to determine whether the topographical propagation of alpha-synuclein is unidirectional or not and the identification of the route of this progression. To do this, the authors used their expertise in inoculating Lewy body extracts containing the misfolded alpha-synuclein protein in non-human primates. The extracts used came from the substantia nigra of parkinsonian patients who gave their brains to science. Using different approaches, the authors elegantly compared the data after 2 years from control baboons or baboons inoculated with these extracts in either the posterior putamen or the intestine. Surprisingly, the two groups of inoculated monkeys showed fairly comparable nigrostriatal dopamine loss, which remained fairly moderate and, in any case, below the threshold for appearance of proven parkinsonian symptoms, along with a significant increase in the levels of misfolded alpha-synuclein in the posterior putamen. Interestingly, in the baboons inoculated directly into the posterior putamen, high levels of the various forms of alpha-synuclein were found not only in the brain but also in the enteric nervous system and the stomach, demonstrating a possible brain-to-gut progression of synucleinopathy. To identify the route of this brain-to-gut progression, the authors looked for regional variations of the phosphorylated or aggregated forms of misfolded alpha-synuclein at the level of the vagus nerve and its dorsal motor nucleus but failed to find any. However, they found a higher concentration of native alpha-synuclein in the blood of all injected monkeys compared to uninjected age-matched controls, which was positively correlated with alpha-synuclein labeling of enteric neurons. Circulating levels of alpha-synuclein might therefore reveal the synucleinopathy or play a role in its propagation. Contrasting with the primate work of Arotcarena and colleagues,2 several rodent studies have demonstrated that the vagus nerve is a key route by which alpha-synuclein pathology can spread both to and from the brain.3, 4 Additionally, truncal vagotomy may be associated with a reduced risk for PD.5 However, not all PD patients adhere to the Braak staging system; the genetic forms of PD show, for example, a distinct pattern of Lewy pathology.6 Propagation of synucleinopathy may therefore vary between PD subtypes, engage alternative routes, and explain clinical heterogeneity of the disease.

The aim of this study was to investigate the causal role of an early serotonin injury on parkinsonian-like motor symptomatology. Monkeys were pretreated with 3,4-methylenedioxy-N-methamphetamine (MDMA, or "ecstasy"), known to lesion serotonergic fibers, before being administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We combined behavioural assessment, PET imaging, and immunohistochemistry. Strikingly, prior MDMA administration aggravated MPTP-induced Parkinsonism and associated dopaminergic injury. Monkeys with early MDMA lesions developed parkinsonian deficits more rapidly and more severely. Interestingly, not all symptoms were impacted. Bradykinesia, rigidity and freezing were not affected by early MDMA lesions, whereas spontaneous activities, tremor and abnormal posture were significantly aggravated. Finally, as expected, MDMA induced a decrease of the serotonergic transporter availability. More surprisingly, we found that MDMA evoked also a decreased availability of the dopaminergic transporter to a lesser extent. Altogether, these results show that MDMA administration in non-human primates not only damage serotonergic terminals, but also injure dopaminergic neurons and enhance MPTP neurotoxic action, a completely new result in primates.

Whether structural alterations underpin apathy and depression in de novo parkinsonian patients is unknown. The objectives of this study were to investigate whether apathy and depression in de novo parkinsonian patients are related to structural alterations and how structural abnormalities relate to serotonergic or dopaminergic dysfunction.