# Pathophysiology of dyskinesia and behavioral disorders in non-human primates

Véronique Sgambato, Léon Tremblay

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Véronique Sgambato, Léon Tremblay. Pathophysiology of dyskinesia and behavioral disorders in non-human primates. Journal of Neural Transmission, 2018, 125 (8), pp.1145 - 1156. 10.1007/s00702-018-1871-7. hal-04845272

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**Pathophysiology of dyskinesia and behavioral disorders in non-human primates.**

Véronique Sgambato<fnref n="1" />,# and Léon Tremblay<fnref n="1" />.

<footnote n="1">¹ Univ Lyon, CNRS, Institut des Sciences Cognitives *Marc Jeannerod* UMR 5229, F-69675 BRON, France
\# *Corresponding author*. E-mail address: veronique.sgambato@isc.cnrs.fr. Phone: +33 (0) 4 37 91 12 49;
Fax: +33 (0) 4 37 91 12 10.</footnote>
The MPTP monkey model of Parkinson's disease (PD) has allowed huge advances regarding the understanding of the pathological mechanisms of PD and L-DOPA-induced adverse effects. Among the main findings were the unbalance between the efferent striatal pathways in opposite directions between the hypokinetic and hyperkinetic states of PD. On both normal and parkinsonian monkeys, the combination of behavioral and anatomical studies has allowed to decipher the cortico-basal ganglia circuits involved in both movement and behavioral disorders. A major breakthrough has then been done regarding the hypothesis of the involvement of serotonergic fibers to convert L-DOPA to dopamine when dopaminergic neurons are dying and to release it, in an uncontrolled manner, as serotonergic neurons are deprived from the machinery required for buffering serotonin from the synaptic cleft. The crucial involvement of serotonergic fibers to underlie L-DOPA-induced dyskinesia (LID) has been demonstrated in the double lesion MPTP/MDMA monkey model of PD, in which dyskinesia induced by L-DOPA are abolished following serotonergic fibers lesion. Moreover, the role of serotonergic fibers goes well beyond dyskinesia, as lesion of such serotonergic fibers by MDMA also decreased the other L-DOPA-induced adverse effects, impulsive compulsive behaviors and visual hallucinations. The same pathological mechanism, i.e. an unbalance between serotonin and dopamine terminals may therefore favor L-DOPA-induced adverse effects according to the basal ganglia territory it takes place. Further non-human primate studies will be needed to demonstrate the role of such pathological mechanism in both movement and behavioral disorders driven by L-DOPA therapy but also to determine the causal link between serotonin lesion and expression of non-motor symptoms like apathy, depression and anxiety, frequently observed in PD patients.
With a prevalence of 150 in 100 000 (Elbaz and Damier, 2004), Parkinson's disease (PD) is the single most common cause of dyskinetic movement disorders. Dyskinesias are common in treated patients, and they indeed represent a major complication of the pharmacotherapy of PD (Voon et al., 2017). The dopamine (DA) precursor, 3,4 dihydroxyphenyl-L-alanine (L-DOPA) remains the most cost-effective treatment for PD (Rascol et al., 2003), but causes motor fluctuations and dyskinesia in 40% of the patients after 4-6 years and up to 90% after 10 years (Ahlskog and Muenter, 2001; Manson and Schrag, 2006). The use of long-acting DA receptor agonists instead of L-DOPA reduces the incidence of motor complications, but these agents achieve a poorer symptomatic control and have important side effects (Stowe et al., 2008). The vast majority of PD patients will therefore continue to require treatment with L-DOPA at some point during the course of the disease. A vast range of abnormal involuntary movements that occur in PD patients receiving dopaminergic pharmacotherapy are grouped under the term, L-DOPA-induced dyskinesia (LID). The risk factors for LID are disease severity and duration, high initial and cumulative doses of L-DOPA, and young age at PD onset (Manson and Schrag, 2006). As the disease progresses, the probability to obtain a good clinical response diminishes and the risk to develop LID and to obtain an unsatisfactory clinical response increase. Discontinuous or pulsatile stimulation of dopaminergic receptors is a key mechanism underlying LID (Olanow et al., 2006). Therefore, LID are a serious limitation in the management of advanced PD patients (Ahlskog and Muenter, 2001). Therefore, the search for an animal model of LID similar to patient's LID was essential to explore pathophysiological mechanisms and to find new therapeutic options.

# 1. L-DOPA-induced dyskinesia and relevance of the MPTP-monkey model of Parkinson's disease

All LID animal models so far described share two prime causative factors, namely, a nigrostriatal DA lesion and pulsatile exposure to L-DOPA. The primate species most commonly used to model PD and LID are species of Old World monkeys, namely African green monkeys (also called the vervet monkey) (*Cercopithecus aethiops*), rhesus (*Macaca mulatta*) and cynomolgus (*Macaca fascicularis*) macaques even
though species of the New world monkeys, the marmosets (*Callithrix jacchus*) and the squirrel (*Saimiri sciureus*) monkeys are used as well (Potts et al, 2014).

Non-human primate (NHP) models of PD have, until recently, been based on the destruction of nigrostriatal dopaminergic neurons using the neurotoxin MPTP (1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine) (see figure 1 and Blesa et al, 2012). This toxin, which leads dopaminergic (DA) neurons death, can be administered via a variety of systemic routes (intramuscularly, intravenously, intraperitoneally or, more rarely, intracarotid, to induce a hemi-Parkinsonian phenotype). A variety of different MPTP administration protocols have been described and are used routinely (i.e., the so-called acute, chronic, and subchronic models), and vary considerably between different primate species. The symptoms can also vary depending on the species and treatment regime used. Notwithstanding the species, MPTP-induced Parkinsonism in NHP is characterized by bradykinesia, rigidity and a slumped body posture with episodic freezing, action tremor (resting tremor being observed only with African green monkey (Guehl et al., 2003). In order to evaluate the severity of motor symptoms, different scales have been developed, e.g., eight scales in the macaque (Imbert et al, 2000). These scales gather different behavioral components, encompassing bradykinesia, posture and tremor. Interestingly, as seen in idiopathic PD, MPTP lesioned NHP may also have cognitive impairment, e.g., visuospatial and planning or strategy deficits (Schneider and Pope-Coleman, 1995; Pessiglione et al., 2004). In the macaque, using progressive or acute MPTP administration paradigms, animals may present transient or persistent motor symptoms, and may therefore be divided into recovered or symptomatic monkeys (Mounayar et al., 2007; Beaudoin-Gobert et al., 2015). There is a clear link between symptomatology severity and DA cell loss (Song and Haber, 2000; Mounayar et al. 2007; Beaudoin-Gobert et al., 2015; Ballanger et al., 2016). This can be detected using a variety of techniques, such as, but not limited to, PET imaging using [¹⁸F]-DOPA or [¹¹C]-PE2I as dopaminergic radioligands (see figure 3) or by using postmortem immunohistochemistry staining for tyrosine hydroxylase-like immunoreactivity (see figure 1). Low dose MPTP exposure actually produces a pattern of nigrostriatal degeneration characteristic of that seen in PD, in which there is a greater depletion of dopaminergic markers in the putamen that in the caudate nucleus (Moratalla et al., 1992; Jan
et al., 2003; Iravani et al., 2005), especially at posterior level. Higher doses or stronger regimens of intoxication, although generating more comprehensive behavioral phenotypes, abolish these differences with more homogenous pattern of denervation in putamen and caudate while the ventral striatum remains less affected (see figure 3 and Bezard et al., 2001; Meissner et al. 2003; Mounayar et al., 2007; Beaudoin-Gobert et al., 2015).

Intermittent L-DOPA treatment to MPTP-intoxicated monkeys induces dyskinetic syndromes (Bédard et al., 1986; Clarke et al., 1987; Crossman, 1987; Schneider, 1989; Bezard et al., 2003; Fox and Brotchie, 2010) that provide the animal equivalent of peak-dose LID, which is correlated to high plasma level of L-DOPA and in parallel with the maximal clinical benefit. Dyskinetic movements can include choreic-athetoid, dystonic and ballistic movements, but, as for parkinsonian symptoms, each monkey will display its own pattern of dyskinetic movements as observed in PD patients. There also may be variation in their physical location with involvement of head, face, jaw, tongue, shoulder, limbs or trunk. The most frequent manifestations are chorea movements of the lower limbs. Several rating scales exist to quantify LID and were reviewed with a focus on macaques (Fox et al., 2012). A link between LID and the extent of the dopaminergic damage has been well documented in NHP. Monkeys with mild parkinsonian symptoms do not develop dyskinesias similar to those produced in the severely affected animals (Schneider, 1989; Boyce et al., 1990; Jenner, 2003). The more symptomatic the monkeys, the highest antiparkinsonian L-DOPA doses required and the most rapid LID development. There is a positive correlation between L-DOPA dose and duration and severity of LID (Jenner, 2003; Beaudoin-Gobert et al., 2015; Morissette and Di Paolo, 2017). Moreover, mildly-DA lesioned monkeys which are able to recover from their motor symptoms never develop LID despite increasing L-DOPA doses (Beaudoin-Gobert et al., 2015), suggesting the existence of a DA lesion threshold and/or pattern required for LID to exhibit. Thanks to its similarities with LID in PD patients, this LID NHP model is ideal to study pathophysiological mechanisms in the basal ganglia (BG) circuits.
## 2. Dyskinesia and behavioral disorders are induced from motor and associative/limbic basal ganglia territories, respectively

BG are interconnected subcortical structures interposed between the cerebral cortex, the thalamus, and premotor centers in the brain stem. They play a central role in behavior through the control of movement and cognitive/motivational processes leading to goal-directed action (Alexander, 1994; Middleton and Strick, 2000; Graybiel, 2005; Tremblay et al., 2015). Their main input structure, the striatum (subdivided into caudate nucleus, putamen and ventral striatum in NHP) receives abundant glutamatergic afferents from almost all the cerebral cortex and from thalamic nuclei. The output nuclei of the basal ganglia consist of the internal pallidal segment (GPi) and the substantia nigra pars reticulata (SNr). These nuclei comprise GABAergic projection neurons that maintain a high level of tonic inhibition onto their thalamic and brain stem targets. Such inhibition needs to be lifted in a spatiotemporally precise manner for a fluid execution of movement sequences (Mink, 1996). Neuronal activities in the GPi/SNr are controlled by the striatum, the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). The STN mainly consists of glutamatergic efferent neurons receiving a direct cortical input ("hyperdirect pathway") and providing an extensive innervation to the GPi/SNr. This hyperdirect pathway plays a critical role in interrupting inappropriate movement preparation (Mink, 1996; Nambu, 2004). Importantly, the STN is strongly interconnected with inhibitory neurons of the GPe (Parent and Hazrati, 1995). The striatum regulates BG output layer via two GABAergic pathways: a direct projection ("direct pathway") and an indirect projection ("indirect pathway") through GPe and STN (see figure 1B and Albin et al., 1989; DeLong, 1990). Striatal efferent neurons giving rise to the direct and indirect pathways have opposite functional roles, facilitating or inhibiting movement, respectively. Nigrostriatal dopaminergic projections oppositely modulate activities in the direct and indirect pathways because of the preferential expression of D1 and D2 receptors, respectively, on the corresponding populations of striatal efferent neurons (Gerfen et al., 1990). In PD, the loss of dopaminergic neurons disturbs the functional organization of BG networks by causing between the two efferent striatal output pathways an imbalance, responsible for akinesia (DeLong, 1990; Obeso et al., 2002).
The current BG anatomo-functional model proposes that LID are caused by reduced activity in the STN and GPi and disinhibition of the thalamocortical projection, as a result of excessive dopaminergic effects on the GPe neurons (Filion et al., 1991; Guridi et al., 2012; Obeso et al., 2014). This could be the result of excessive inhibition by the GPe following removal of the inhibitory tone that dopamine exerts on the GABAergic striato-pallidal projection (see figure 1B-C). A direct demonstration of the link between short acting dopaminergic stimulation and changes in BG output was provided by Filion and collaborators (1991, see figure 1C). It was shown that apomorphine (a DA agonist) administration in parkinsonian monkeys induced dyskinesias which were associated with a reduction in the firing rate of GPi neurons and an increase in the firing rate of GPe neurons (see figure 1C and Filion et al., 1991). The striato-pallidal pathway from the indirect BG circuits has been involved in dyskinesia as manipulation of sensorimotor territories of both pallidal segments, putamen and STN further evoke dyskinetic movements in normal and parkinsonian monkeys (see Figure 1C; Crossman et al., 1980; 1984; Crossman, 1987; Matsumura et al. 1995; Karachi et al., 2009; Sgambato-Faure and Cenci, 2012 for review). For GPi, injection of muscimol, a GABAergic agonist (Burbaud et al., 1998) evoke choreic type of dyskinesia. Microinjections of bicuculline, a GABAergic antagonist, in the GPe and postero-medial putamen was found to elicit chorea of the contralateral limbs and/or orofacial region, while microinjections in the lateral part of the putamen elicited contralateral myoclonus (Crossman et al., 1988; Matsumura et al., 1995; Grabli et al., 2004). Unilateral excitotoxic lesions in the posterior putamen produced marked dystonia and dyskinesia after apomorphine administration, while bilateral selective lesion in the posterior putamen resulted in marked spontaneous chorea and persistent apomorphine-induced dyskinesia thereafter (Burns et al., 1995; Hantraye et al., 1990). Finally, abnormal movements are also triggered by bicuculline microinjections (Worbe et al., 2009) or by discontinuous microstimulation (Worbe et al., 2011) in the posterior putamen. Taken together, these studies indicate that abnormal movements with choreic or hyperkinetic features can be elicited by local neuronal hyperactivities or dysfunction of the sensorimotor territories of the basal ganglia. By combining reversible pharmacological perturbation with monosynaptic tracer injection, the
cortico-BG circuit underlying dyskinesia expression was identified (See Figure 2A, and François et al., 2004; Worbe et al., 2009 and Galineau et al., 2017).

Just as dyskinesia can be induced by a dysfunction of BG sensorimotor territories, a similar dysfunction inside the limbic/associative BG territories will trigger behavioral disorders (Figure 2). In other words, if the increased firing rate of sensorimotor GPe neurons abolishes the firing rate of sensorimotor GPi neurons, releasing neurons from the ventrolateral thalamus and from somesthetic and parietal cortices, the same process, when applied to another territory, should lead to the same releasing effect on others cortical area. Microinjections of bicuculline in the limbic or associative part of the GPe induce compulsive behaviors or a hyperactive state typical of impulsive disorders, respectively (Grabli et al., 2004; Saga et al., 2017; Galineau et al., 2017). Local disinhibition in the limbic territory of the striatum triggers abnormal behaviors such as sexual manifestations, aversive behaviors and reduction of self-initiated action associated with loss of food motivation (Worbe et al., 2009; Sgambato-Faure et al., 2016). Discontinuous stimulation of the associative/limbic part of the anterior striatum also evokes abnormal behaviors (Worbe et al., 2011). Impulsive disorders are triggered from the dorsolateral part (see figure 2B; green territories), hypoactive state with feeding disturbance from the ventrolateral part and compulsive disorders from the central part of the ventral striatum (VS) and the ventral pallidum (VP) (see figure 2B; blue territories). Moreover, local disinhibition in the associative and limbic territories of STN induces similar complex behavioral disorders with compulsive and impulsive features (Karachi et al., 2009). Finally, dysfunction of an associative cortico-BG circuit may underlie L-DOPA-induced visual hallucinations, which are commonly found in advanced PD patients treated with L-DOPA (Diederich et al., 2005; Williams and Lees, 2005) and which have been modeled and studied on the NHP (Visanji et al., 2006; Fox et al., 2010; Beaudoin-Gobert et al., 2015). As illustrated in figure 2C, such circuit may involve the direct projection from the inferotemporal cortex to the associative BG territories which project back to the temporal cortex via the thalamus (Middleton and Strick, 1996). The inferotemporal cortex is indeed involved in the visual recognition and discrimination of objects (Baizer et al., 1993; Middleton and Strick, 1996, Kim and Hikosaka, 2015). Dysfunction of this loop may lead to alterations in visual perception,
including visual hallucinations. To summarize, these studies indicate that behavioral disorders can be
triggered by local manipulations of the associative/limbic territories of the basal ganglia. These results
support a pivotal role of cortico-basal ganglia circuits in generating many motor and behavioral
abnormalities that occur in common neurodegenerative diseases and psychiatric disorders (Tremblay et al.,
2015). The dysfunction of such circuits, driven by dopaminergic lesion and pharmacotherapy with L-
DOPA or long-acting DA agonists, favor the risk for PD patients to develop a wide range of behavioral
disorders such as impulsive compulsive disorders and visual hallucinations.

3. Involvement of serotonin fibers in L-DOPA adverse effects (LID and ICD)

Striatal serotonin projections have been implicated in LID by transforming L-Dopa in DA and
increasing the DA release (without DA vesicular storage) via serotonin axon terminals in both primate and
human striatum (Rylander et al., 2010; for reviews Carta and Tronci, 2014; Bastide et al., 2015). To more
closely mimic the DA and 5-HT lesions occurring in the brains of parkinsonian patients (Huot et al., 2011;
Politis, 2014; Politis and Niccolini, 2015), and demonstrate the causal role of the serotonergic fibers in
LID, we have developed a double DA/5-HT lesion monkey model of PD (Beaudoin-Gobert et al., 2015).
This model consists of administrating MDMA (also known as Ecstasy) to previously MPTP-intoxicated
monkey. MDMA is an amphetamine derivative with high SERT affinity (Battaglia and De Souza, 1989)
which acutely induces massive release of 5-HT (Rudnick and Wall, 1992; Gough et al., 1991) and
chronically lesions serotonergic terminal fibers (Karuppagounder et al., 2014). The neurotoxic effects of
MDMA on 5-HT have been described in the normal primate in several species, including the macaque
(Ricaurte et al., 1988; 2000; Insel et al., 1989; 2000; De Souza et al., 1990; Hatzidimitriou et al., 1999;
Szabo et al., 2002) and in humans, diffusion-tensor imaging studies have shown that MDMA impacts
axonal integrity, notably in the thalamus (De Win et al., 2008). We have extended those studies by showing
that MDMA is an efficient tool to ubiquitously lesion 5-HT fibers in the brain of MPTP-parkinsonian
monkeys (See figure 3 and Beaudoin-Gobert et al., 2015; Météreau et al. 2017). Thanks to this model, we
have demonstrated for the first time that 5-HT fibers mediate LID in NHP (see figure 3A-B and Beaudoin-
Gobert et al., 2015). Specifically, LID are only expressed when high SERT levels are found in the posterior putamen and raphe, highlighting the crucial role of serotonin sprouting and consequent high SERT/DAT ratio taking place in such sensorimotor BG regions (figures 3 and 4). In agreement with those findings, there is also a beneficial role of administrating 5-HT₁A or 5-HT₁A/B agonists systemically in dyskinetic monkeys (Munoz et al., 2008) or parkinsonian patients (Politis et al., 2010; 2014), highlighting again the deleterious role of striatal presynaptic 5-HT fibers (Rylander et al., 2010; Carta and Tronci, 2014; Cenci, 2014; Politis et al., 2014). Besides the striatum, LID in PD patients are positively correlated with higher serotonergic function in both pallidal segments (Smith et al., 2015). This may result in further dysregulation of thalamocortical signals and therefore contribute to the expression of dyskinesias. Finally, as the inclusion of 5-HT neurons in the grafted foetal dopamine transplant significantly worsens LID in the rat model of PD (Carta and Tronci, 2014), particular attention has been focused on the possible influence of the DA/5-HT ratio detected on LID expression. Dyskinetic monkeys had a higher putaminal [¹¹C]DASB / [¹¹C]PE2I ratio compared to non-dyskinetic ones (figure 4 and Beaudoin-Bobert et al., 2015). Interestingly, the putaminal SERT/ DAT ratio increases as PD progresses and patients experience LID (Roussakis et al., 2016), corroborating findings in grafted PD patients, which present a higher putaminal SERT/ DAT ratio as well (Politis et al., 2011) and whose dyskinesia are mediated by 5-HT neurons (Politis et al., 2010).

One striking and unexpected result we have obtained is that recovered MPTP-treated monkeys chronically treated with L-DOPA did not develop dyskinesias, but rather hyperactive and neuropsychiatric-like behaviors. These abnormal behaviors in response to L-DOPA were assessed with the scale developed in the marmoset and allowing to score agitation (hyperkinesia, vocalization), hallucinatory-like response behaviors to non-apparent stimuli (tracking, staring), compulsive grooming (scratching, grooming) and stereotypias (side-to-side jumping, head checking, purposeless running, fiddling with bars) (Visanji et al., 2006; Fox et al., 2010). Noteworthy, neuropsychiatric-like behaviors were abolished by subsequent MDMA lesion (See figure 3C-D). These findings are particularly interesting as it demonstrates that serotonergic fibers also play a significant role in the pathophysiology of non-motor symptoms driven by L-DOPA (see figure 4 and Beaudoin-Gobert et al. 2015). As recovered monkeys are the ones exhibiting a
sprouting of 5-HT fibers after MPTP (Mounayar et al., 2007; Beaudoin-Gobert et al., 2015), one can speculate that these fibers sustain the expression of behavioural disorders via aberrant processing of exogenous L-DOPA and release of dopamine as false neurotransmitter in non-motor regions (antero-ventral striatum and ventral Pallidum; see figure 2B and 3C), as it is the case in motor regions (posterior putamen or posterior GPe; see figure 2A and 3B) for L-DOPA-induced dyskinesias (Figure 4 and Politis et al., 2014). Among our main results figure the positive correlation found between the presynaptic 5-HT innervation in the posterior ventral putamen and the severity of the hallucinatory-like response (Figure 2C). Atypical antipsychotic, quietapine and clozapine reduce L-DOPA-induced psychosis and psychotic-like behaviour without a significant increase in parkinsonian disability (Fox et al., 2008; Gottwald and Aminoff, 2011). An alteration of the 5-HT system on this ventral visual Cortico-BG circuit ending in the temporal cortex may explain the changes in 5-HT2A receptors in the temporal cortex observed in PD patients expressing visual hallucinations (Ballanger et al. 2010; Huot et al., 2010). The slower degeneration of serotonergic (versus dopaminergic) terminals as Parkinson's disease progresses could therefore be a risk factor for occurrence of these L-DOPA-induced non-motor symptoms, which remain a major challenge in treating patients with advanced PD (Figure 4).

## Conclusions and perspectives of NHP model of PD

The NHP model of PD using the MPTP to induce DA lesion has been very important to understand the pathophysiology of PD symptoms but also those behind LID. The new NHP model of PD with double DA and 5-HT lesions by using MDMA to add a wide 5-HT terminals lesion to the MPTP-induced DA one, has provided an important conceptual advance by demonstrating that lesioning the presynaptic serotonergic fibers abolishes both LID and neuropsychiatric-like behavior in the macaque model of PD. L-DOPA-induced complications may share similar pathophysiological mechanisms (See Figure 4, and Bastide et al., 2015). Due to lesion severity and L-DOPA treatment, it is possible that serotonergic fibers release DA as a false neurotransmitter not only in the putamen but also in other BG regions, contributing to a risk factor to develop, to different extents, L-DOPA-induced complications. When the increased SERT/DAT ratio is
experimentally counteracted by MDMA, there is an abolition of LID and neuropsychiatric disorders, highlighting the importance of the balance existing between dopaminergic and serotonergic fibers. Another important feature of this model is that by reversing the sequential use of the toxins (MDMA before MPTP), one can address the impact of an early serotonergic lesion on the appearance and severity of the parkinsonian motor and non-motor symptoms. Therefore, this double-lesioned model opens important new preclinical research avenues that may lead on new potential therapeutic targets. Finally, outside of the context of PD, these findings highlight the possibility that serotonergic fibers may play a deleterious role not only in movement disorders but also in behavioural disorders.

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Figures legend:

**Figure 1:** Pathophysiology of L-Dopa-induced dyskinesia on MPTP-primate model of Parkinson's disease. (A) Cortico-BG circuit & MPTP-driven SNc lesion. Note the dopaminergic cell loss after MPTP treatment at the level of the substantia nigra when comparing the coronal sections from normal and MPTP monkeys. (B) Model of Direct/indirect Pathways and GPe role in LID. Note that dyskinesia is underlined by an overactivity of the external segment of the globus pallidus which induces an overactivity of the thalamocortical pathway via overinhibition of the internal segment of the globus pallidus. (C) Sensorimotor territories, Striatal DA-lesion and basal ganglia dysfunction behind LID. Dyskinetic movements can be induced in the MPTP-intoxicated monkey by a dopaminergic treatment, which induces opposite pattern of activity in both pallidal segments. The same type of dyskinesia as LID was produced on normal monkey by recreating the overactivity of GPe neurons by injection of bicuculline (GABAergic antagonist) in the sensorimotor territory of this structure showing the causal link between GPe overactivity and LID (Matsumura et al. 1995 and Grabli et al. 2004). Abbreviations: SNc, substantia nigra pars compacta; VTA, ventral tegmental area; CdN, caudate nucleus; Put, putamen; Thal, thalamus; GPi, internal segment of the globus pallidus; GPe, external segment of the globus pallidus; SNc: Substantia nigra pars compacta; STN, subthalamic nucleus; SM, sensorimotor; Limb, limbic; DA, dopamine; bicu, bicuculline; LID, L-DOPA-induced dyskinesia.

**Figure 2:** Cortico-BG circuits involved in (A) Dyskinesia, (B) Impulsive-compulsive disorders and (C) L-DOPA-induced Visual Hallucinations. (A) The sensorimotor territories (in yellow) of BG and cortical areas involved in dyskinesia were identified by François et al., 2004; Worbe et al., 2009 and Galineau et al., 2017; (B) The associative (in green) and limbic (in blue) territories of BG and cortical areas respectively involved in impulsive and compulsive disorders came from NHP studies performed by François et al., 2004; Sgambato-Faure et al.; 2016 and Galineau et al., 2017. (C) The hypothesis of cortico-BG circuit (in green) involved in L-DOPA-induced visual hallucinations came from the convergence of
anatomical (Middleton and Strick, 1996), physiological (Kim and Hikosaka, 2015) and lesional (Beaudoin-Gobert et al., 2015) NHP studies. Abbreviations: AC: Anterior commissure; ACC: Anterior cingulate cortex; Amyg: Amygdala; CdN: Caudate nucleus; GPe: external segment of Globus Pallidus; GPi: internal segment of Globus Pallidus; Ins: Insula; LPFC: Lateral prefrontal cortex; MC: Motor Cortex; MPFC: Medial prefrontal cortex; OFC: Orbitofrontal cortex; PC: Parietal cortex; PMC: Premotor cortex; Put: Putamen; SC: Somesthetic cortex; SMA: Supplementary motor area; SNc: Substantia nigra pars compacta; SNr: Substantia nigra pars reticulata; STN: Subthalamic nucleus; TC: Temporal cortex; TE: Inferotemporal cortex; Thal: Thalamus; VA: Ventral anterior; VL: Ventral lateral; VM: Ventral medial; VP: Ventral pallidum; VS: ventral striatum.

**Figure 3: Involvement of DA and 5-HT presynaptic systems in (A-B) L-DOPA-induced dyskinesia and (C-D) L-DOPA-induced impulsive compulsive disorders.** MRI-fused PET images on horizontal (left and middle) and sagittal (right) planes showing the cerebral distribution of [¹¹C]-PE2I (for the dopaminergic transporter) on the left and of [¹¹C]-DASB (for the serotonergic transporter) on the right with or without L-DOPA-induced adverse effects. Colors represent the level of the non-displaceable binding potential (BPND) using the cerebellum as the reference region (red indicates high BPND whereas pink indicates low BPND). (A) Comparison between control and PD state after MPTP which shows the DA lesion and 5-HT plasticity that allows LID expression. It should be noted an increase of SERT levels in the raphe and posterior putamen, where DA fibers are most affected. (B) A reduction of these 5-HT terminals by MDMA in the raphe and the posterior putamen abolished LID. (C) Comparison between control and ICD state after MPTP which shows the DA lesion and 5-HT plasticity that allows ICD expression. It should be noted an increase of SERT levels in the raphe, ventral posterior putamen and ventral pallidum. (D) A reduction of 5-HT terminals by MDMA in these regions abolished ICD. Note also that, compared to LID, ICD is linked to a more moderate striatal DA lesion but to a 5-HT plasticity in the ventral pallidum.

Abbreviations: post put, posterior putamen; str, striatum; VP, ventral pallidum; VS, ventral striatum; LID, L-DOPA-induced dyskinesia; ICD, impulsive compulsive disorders.
**Figure 4: Critical role of 5-HT / DA balance in L-Dopa-induced complications.** (A) In the normal condition, serotonin is synthetized from the 5-hydroxytryptophan thanks to the amino-acid decarboxylase expressed by serotonergic neurons. Serotonin is released from 5-HT terminals in the synaptic cleft, from where it can be reuptaken by the serotonergic transporter or by 5-HT₁A/B autoreceptors. Dopamine is synthetized from L-DOPA thanks to the same enzyme which is also expressed by dopaminergic neurons. Dopamine is released from DA terminals in the synaptic cleft, from where it can be reuptaken by the dopamine transporter or dopaminergic D2 autoreceptors. (B and D) After MPTP intoxication followed by L-DOPA treatment, there is a loss of dopaminergic fibers while there is a sprouting of serotonergic terminals, corresponding to a high SERT / DAT ratio. As a consequence, L-DOPA is majorly transformed into dopamine via serotonergic terminals which do not express the machinery able to clean dopamine from the synaptic cleft. As a consequence, there is an increase of dopamine levels and a decrease of serotonin levels, a situation which favors the risk for L-DOPA-induced adverse effects. (C and D) MDMA destroys the serotonergic terminals, restoring a low SERT / DAT ratio and low dopamine levels, a situation in which there is a low risk for L-DOPA-induced adverse effects. (D) Depending on the basal ganglia structures and territories in which the SERT / DAT ratio is unbalanced (towards a high ratio), different L-DOPA-induced adverse effects can be induced: dyskinesia when the posterior putamen or posterior pallidum is affected; impulsive compulsive disorders when the ventral striatum or the anterior pallidum is affected; hallucinations when the ventral posterior putamen or the ventral external pallidum is affected. Abbreviations: 5-HT, serotonin; 5-HTP, 5 hydroxytryptophan; AADC, aminoacid decarboxylase; SERT, serotonin transporter; DA, dopamine; DAT, dopamine transporter; post, posterior; put, putamen; VS, ventral striatum; GPe, external segment of the pallidum; LID, L-DOPA-induced dyskinesia; ICD, impulsive compulsive disorders; VIH, visual hallucinations.

**Funding**

This work was supported by grants from Fondation de France (grant numbers 201234497 and 00016818) and Labex Cortex (ANR-11-LABX-0042).
**Conflict of interest**

The authors declare that they have no conflict of interest.

**Ethical approval**

All applicable international, national, and/or institutional guidelines for the care and use of animals were
followed.

**Acknowledgments**

Dr V. Sgambato is supported by INSERM (Institut National de la Santé et de la Recherche Médicale) and
Dr L Tremblay by CNRS (Centre National de Recherche Scientifique).
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<figure><img src="image_10.png" /><figcaption>Figure 1</figcaption></figure>
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