EXCLI Journal 2020;19:268-295 – ISSN 1611-2156 Received: January 03, 2020, accepted: February 24, 2020, published: March 02, 2020

Review article:

SEROTONERGIC SYSTEM MODULATION HOLDS PROMISE FOR L‐DOPA‐INDUCED DYSKINESIAS IN HEMIPARKINSONIAN RATS: A SYSTEMATIC REVIEW

Fereshteh Farajdokht1, 2, Saeed Sadigh-Eteghad2, Alireza Majdi2, Fariba Pashazadeh1,3, Seyyed Mehdi Vatandoust2, Mojtaba Ziaee4,5, Fatemeh Safari6, Pouran Karimi2, Javad Mahmoudi2*

1 Research Center for Evidence-Based Medicine (EBM), Health Management and Safety Promotion Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran 2 Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran 3 Iranian Evidence-Based Medicine (EBM) Center, a Joanna Briggs Institute Affiliated Group 4 Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 5 Phytopharmacology Research Center, Maragheh University of Medical Sciences, Maragheh, Iran 6 Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran

* Corresponding author: Dr. Javad Mahmoudi, Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran, Postal code: 5166614756, Iran, Tel: +984133351284, E-mails: [email protected], [email protected]

http://dx.doi.org/10.17179/excli2020-1024

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).

ABSTRACT The alleged effects of agents in alleviating levodopa-induced dyskinesias (LIDs) in parkinsonian patients are debatable. To this end, we systematically reviewed the serotonergic agents used for the treatment of LIDs in a 6-hydroxydopamine model of Parkinson’s disease in rats. We searched MEDLINE via PubMed, Embase, Google Scholar, and Proquest for entries no later than March 2018, and restricted the search to publications on serotonergic agents used for the treatment of LIDs in hemiparkinsonian rats. The initial search yielded 447 cita- tions, of which 49 articles and one conference paper met our inclusion criteria. The results revealed ten different categories of serotonergic agents, including but not limited to 5-HT1A/BR , 5-HT2AR antagonists, selective reuptake inhibitors (SSRIs), serotonin-norepinephrine (SNRIs), and (TCAs), all of which improved LIDs without imposing considerable adverse effects. Although there is promising evidence regarding the role of these agents in relieving LIDs in hemiparkinsonian rats, further studies are needed for the enlightenment of hidden aspect of these molecules in terms of mechanisms and out- comes. Given this, improving the quality of the pre-clinical studies and designing appropriate clinical trials will help fill the bench-to-bedside gap.

Keywords: L-DOPA, levodopa-induced dyskinesias, 6-hydroxydopamine, rat, serotonergic system

268 EXCLI Journal 2020;19:268-295 – ISSN 1611-2156 Received: January 03, 2020, accepted: February 24, 2020, published: March 02, 2020

INTRODUCTION for human via providing evidence for the de- sign of clinical trials. However, we increas- Levodopa (L-DOPA) is, by far, the most ingly become aware of the limitations and effective therapeutic option for Parkinson’s weaknesses of pre-clinical studies, causing disease (PD). Despite being a well-tolerated failure during replication of the results from , L-DOPA induces abnormal in- bench to bedside or the “reproducibility cri- voluntary movements (AIMs) in several pa- sis” (Begley and Ioannidis, 2015). Systematic tients following chronic exposure, commonly reviews of animal studies are detailed, com- known as levodopa-induced dyskinesia prehensive, and planned search of the availa- (LIDs) (Politis et al., 2014). The mechanisms ble literature aimed at answering a particular by which L-DOPA induces motor fluctua- question and reducing bias via detecting and tions are yet unclear. Nevertheless, some hy- classifying all relevant data. Although sys- potheses have been put forward explaining tematic reviews of clinical data are exten- the phenomenon; such as significant dopa- sively available, there exists a paucity regard- mine (DA) swings in the brain caused by a va- ing the pre-clinical studies. It has been riety of cells (presynaptic hypothesis) along proposed that systematic reviews can increase with altered signal-transduction in striatal the so-called “experimental rigor” and the neurons and abnormal responses in dopa- quality of the animal studies and improve minoceptive neurons (postsynaptic hypothe- translational studies reproducibility (Uman, sis) (Cenci, 2014). 2011). This systematic review aimed at find- Several studies have confirmed the role of ing the old and most up-to-date serotonergic serotonergic raphe-striatal neurons in L- DOPA-induced LIDs (Prinz et al., 2013; system-based therapeutics for L-DOPA‐in- Tronci and Carta, 2013). Evidence suggests duced dyskinesia in hemiparkinsonian rats. that serotonergic neurons of the central nerv- ous system (CNS) convert orally adminis- METHODS tered L-DOPA to (Navailles et al., Search strategy 2010). These neurons may have a role in the We undertook an electronic search of dysregulated metabolism of exogenous L- computer bibliographic databases of DOPA and consequently the aberrant striatal MEDLINE via PubMed, Embase, Cochrane, release of dopamine in PD patients with LIDs and ProQuest using the keywords “6- (Kannari et al., 2006; Maeda et al., 2005). hydroxydopamine”, “dyskinesias”, “L- Studies performed on rodents and primates DOPA”, “L-dopa-induced Dyskinesia”, have found that modulation of serotonergic “serotonergic”, “5-HT”, and “serotonine” as activity using 5-HT receptor type 1A and 1B follows; (((((((Dyskinesia[Title]) OR (5-HT1A and 5-HT1B ) agonists such as Dyskinesia[Title/Abstract])) AND ((((L- and , acute 5-HT dopa[Title/Abstract]) OR L-dopa[Title]) OR transporter (SERT) blockade, or elimination Levodopa[Title/Abstract]) OR Levodopa of serotonin (5-HT) afferent terminals may [Title]))) OR ((((((L-dopa induced reduce the severity of LIDs without Dyskinesia[Title/Abstract]) OR L-dopa- exacerbating PD manifestations (Bezard et induced Dyskinesia[Title/Abstract]) OR al., 2013b; Conti et al., 2014; Eskow et al., Levodopa-induced Dyskinesia[Title/ 2007; Munoz et al., 2008). Although these Abstract]) OR L-dopa induced Dyskinesia strategies have yielded promising results in [Title]) OR L-dopa-induced Dyskinesia the laboratory, their effects have been barely [Title]) OR Levodopa-induced Dyskinesia investigated in the clinic, which might be due [Title]))) AND ((((5-HT[Title/Abstract]) OR to the uncertainty about the impacts of these serotonine[Title/ Abstract]) OR 5-HT[Title]) in PD patients. OR serotonine [Title]). Also, we manually Pre-clinical animal studies play a crucial searched the bibliographies of retrieved role in the development of novel therapeutics articles in order not to miss any reports in this

269 EXCLI Journal 2020;19:268-295 – ISSN 1611-2156 Received: January 03, 2020, accepted: February 24, 2020, published: March 02, 2020

regard. Two independent investigators 49 articles and one conference paper met our screened the title, abstract, and where neces- inclusion criteria. Figure 1 shows our search sary, the full texts judging them against the strategy and study selection process. We inclusion and exclusion criteria. All further divided the included studies into 12 disagreements were resolved by the third different categories, based on the mechanism investigator. Our search was limited to publi- of action of the drugs used, as follows; several cations in English and other (i.e., non-human) serotonin 5-HT receptors (n=1), dual animals. We did not have any time re- D2/serotonin 5-HT1AR agonist (n=1), dual strictions. D1/2 and 5-HT1AR agonist (n=1), 5-HT1BR agonist (n=2), mixed 5-HT1A&BR agonist Selection criteria (n=11), 5-HT1AR agonists including ‘biased We included all experimental studies that agonists’ and partial agonists (n= 27), were reported in full-text publications or con- serotonin-norepinephrine reuptake inhibitors ference papers and used 6-hydroxydopamine (SNRIs) (n=1), selective serotonin reuptake to induce PD, L-DOPA as a treatment for PD, inhibitors (SSRIs) (n=7), tricyclic and serotonergic system-based therapeutics antidepressants (TCAs) (n=1), 5HT2A/C and for the attenuation of LIDs in rats. The D2/3R antagonist (n=1), 5-HT2AR antagonists primary outcome measure was to find all (n=1), and serotonin neuron transplants (n=1). serotonergic system-based therapeutics used Because some studies tested the effects of for LIDs and the secondary outcome measure more than one serotonergic compound, they was to assess their effects in this regard. were placed in more than one category, and We excluded studies performed on the total number of studies appears to be more species other than rat (mice and primates) and than 50. We also found that the most those that used models other than 6- commonly used therapeutic agents were 5- hydroxydopamine (i.e., MPTP). We also HT1AR agonists (n=27) (Table 1). excluded all ex vivo or in vitro (primary culture or cell line) studies. Further, studies Methodological characteristics that applied non-serotonergic system-based The methodological features of the therapeutics (i.e., glutaminergic, adrenergic, included publications were evaluated in 8 etc.) were excluded. different domains according to modified CAMARADES’ study quality checklist (see Quality assessment above and Table 2). The methodological quality of the in- According to the nature of this study and cluded studies was assessed using a modified its exclusion criteria, all of the included version of the CAMARADES’ study quality publications were published in peer-reviewed checklist. This checklist includes items such journals (n=49). Less than half of the included as the statement of inclusion and exclusion of studies had performed randomization to animals from the study, blinded assessment of treatment or control, and allocation outcome, sample-size calculation, and publi- concealment (n=16 and n=21, respectively). cation in peer-reviewed journal, However, blind assessment of the outcome randomization to treatment or control, state- was performed in a rather high number of ment of compliance with regulatory require- studies (n=31). Only twenty-six studies ments, allocation concealment, and statement specified the statement of inclusion and regarding possible conflict of interest. exclusion of animals, and sample-size calculation was performed in none of the RESULTS included studies. All of the included studies complied with regulatory requirements for General study characteristics The search for computer bibliographic animal housing. Also, a low number of these databases yielded 447 citations, out of which studies (n=20) had the statement of financial

270 EXCLI Journal 2020;19:268-295 – ISSN 1611-2156 Received: January 03, 2020, accepted: February 24, 2020, published: March 02, 2020

Figure 1: Flowchart of studies selection based on the PRISMA statement for the systematic review.

disclosure or conflict of interests. In general, kinsonian rats without affecting L-DOPA ef- the total quality score of the included ficacy and developing tolerance (Thomsen publications was found to be modest (4.3 out and Hansen, 2013). of 8) ranging between 2 and 7. Dual D2/serotonin 5-HT1AR agonists OUTLINE OF INDIVIDUAL Only one publication assessed the impacts THERAPEUTICS of (6aR)-11-amino-N-propyl-noraporphine (SOMCL-171) on LIDs in hemiparkinsonian Several serotonin 5-HT receptors agonist One publication (a conference paper) in- rats. This medication was found to improve vestigated the impacts of JM-010, which is a LIDs, including axial, limb and orolingual dyskinesias in a 21-day course of admin- 5-HT1A, 5-HT1D, 5-HT1B, and 5-HT1FRs ago- nist, on the severity of LIDs. This study did istration without changing the anti-PD effi- not specify the dosage and duration of the cacy of L-DOPA. This study showed that treatment with JM-010. However, it found SOMCL-171 injection to hemiparkinsonian that its acute and chronic administration re- rats activated 5-HT1AR and remarkably in- duced the presentation of AIMs in hemipar- creased its mRNA expression in the 6-hy- droxydopamine-lesioned striatum, both of which contributed to its anti-LIDs effects (Zhao et al., 2014).

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Table 1: Characteristics of studies investigating the effects of a serotonergic system-based medication on LIDs in 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference Combined impacts on several serotonin Thomsen and Several serotonin 5- Safe and effective on 5-HT receptors, in- Acute and JM-010 NM NM Hansen, HT receptors agonist improving LIDs cluding 5-HT1A, 5- chronic 2013 HT1D, 5-HT1B and 5- HT1F receptors Improvement of LIDs 5-HT1A agonistic ac- Dual D2/serotonin 5- with no change in the tivity and the up- 1, 2, or 5 Zhao et al., SOMCL-171 21 days i.p. HT1AR agonist antiparkinsonian effi- regulation of the mg/kg 2014 cacy striatal 5-HT1AR Antidyskinesia ef- fects via both dopa- Acute: single Dual D1/2 and 5- l-stepholidine Significant relief of mine (D2 receptor dose Mo et al., 10 mg/kg i.p. HT1AR agonist (l-SPD) dyskinesia antagonistic activity) Chronic: 22 2010 and restoration of 5- days HT1AR mRNA level No effect on rota- 2.5 and 3.5 Inden et al., CP94253 - Single dose i.p. tional behavior mg/kg 2012 5-HT1BR stimulation 5-HT1BR agonist and accordingly re- Every 2–4 days 1.5 or 3.0 Jaunarajs et CP94253 Mitigation of LIDs duction of D1 recep- but for unde- s.c. mg/kg al., 2009 tor-mediated dyski- fined times nesia Enhancement of ser- Displacement of L- Acute: 6, 12, otonergic tone and DOPA-derived DA 24 and 48 Two weeks 5-HTP improvement LIDs storage into sero- mg/kg i.p. Tronci et al., with no change in the tonergic vesicles & Chronic: 24 2013 Single dose antiparkinsonian effi- activation of seroto- mg/kg Mixed 5-HT1A&BR Eltoprazine cacy nin 5-HT1R 0.3 mg/kg 2 weeks s.c. agonist Presynaptic reduc- tion of DA release Dose-dependent re- 0.1-0.6 Pinna et al., Eltoprazine through activation of 19 days s.c. duction of AIMs mg/kg 2016 serotonergic recep- tors

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Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference Attenuation of LIDs- associated eleva- tion of striatal pERK Prevention of LIDs and neurotransmit- Paolone et Eltoprazine 0.3 mg/kg 21 days i.p. development ter (glutamate) al., 2015 changes in striatum and sunthalamic nu- cleus Extremely effective in Acute: Single suppression of dyski- Mixed 5-HT1A/1BR 0.3 and 0.6 dose Bezard et al., Eltoprazine nesia with partial s.c. stimulation mg/kg Chronic: 3 2013b worsening of the L- weeks DOPA effect Reestablishment of LTP and synaptic depotentiation in SPNs of the stria- tum and subse- quent regulation of Ghiglieri et Eltoprazine Reduction of AIMs D1 receptor-depend- 0.6 mg/kg One week s.c. al., 2016 ent cAMP/PKA and ERK/mTORC signaling pathways, and modulation of NMDA receptor subunits balance Dampening of LIDs 0.05, 0.1, 0.2 Eltoprazine Decrease in seroto- Acute and s.c. by chronic co-admin- mg/kg Tronci et al., nin neuron activity chronic for 19 istration of 5-HTP 12, 24, 48 2015 5-HTP by 5-HT1R days i.p. and eltoprazine mg/kg Preferential activa- tion of 5-HT1BR Dose-dependent re- 0.1, 0.5, 2 Bezard et al., Anpirtoline subtype and control Single dose s.c. duction of LIDs mg/kg 2013a of glutamate and GABA release Combination of Synergistic effect on Modulation of pre- OH-DPAT at Munoz et al., Two weeks s.c. ±8-OH-DPAT suppressing LIDs synaptic release of 0.05 mg/kg 2008

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Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference (1A)/CP-94253 DA from the seroto- dose, CP- (1B) nin terminals 94253 at 1.0 mg/kg Selective dampen- Combination of ing of serotonin- 0.035/0.75, ±8-OH-DPAT Synergistic effect on neuron-dependent 0.05/1.0 Carta et al., Single dose s.c. (1A)/CP-94253 suppressing LIDs DA release from and 0.1/1.75 2007 (1B) striatal serotonergic mg/kg terminals Stimulation of Combination of Significant reduction postsynaptic 5- 0.035/0.75 ±8-OH-DPAT of the AIMs using Iderberg et HT1A/1BR either in and 0.05/1.0 Single dose s.c. (1A)/CP-94253 higher dose combi- al., 2013 the motor cortex or mg/kg (1B) nation the striatum

Combination of Reducing release of Significant decrease ±8-OH-DPAT L-DOPA-derived DA 0.05/1.0 and Munoz et al., in L-DOPA-induced Two weeks s.c. (1A)/CP-94253 from the serotonin 0.1/1.75 2009 AIMs (1B) neurons

Stimulation of 5- HT1A somatoden- dritic autoreceptors Inhibition of an in- and reduction of the Tomiyama et ±8-OH-DPAT 1 mg/kg Two weeks i.p. crease in LIDs activity of sero- al., 2005 tonergic neurons in 5-HT1AR agonists the dorsal raphe nu- including ‘biased cleus agonists’ and partial Activation of 5- agonists Decrease in the in- HT1AR, and subse- stance of LIDs and quent prevention of Nahimi et al., ±8-OH-DPAT alteration of their L-DOPA-induced 0.6 mg/kg Single dose i.p. 2012 temporal pattern displacement of [11C] (DA tracer)

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Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference Responses are Acute: Single Elimination of LIDs mediated dose Ba et al., ±8-OH-DPAT and reduction of the 1 mg/kg i.p. via the 5-HT1A auto- Chronic: 22 2007 failures to L-DOPA receptor days 5-HT1AR-mediated 0, 0.1, 1 i.p. Dose- and receptor- suppression of ipsi- mg/kg Bishop et al., ±8-OH-DPAT dependently de- lateral c-fos immu- Single dose 5, or 10 µg/ 2009 creased LIDs noreactivity and Intrastriatal side PPD mRNA Suppression of L- Responses are Inden et al., ±8-OH-DPAT DOPA-induced rota- mediated via the 5- 1 mg/kg Single dose i.p. 2012 tional behavior HT1A autoreceptor Systemic and in- trastriatal 5-HT1AR Dupre et al., ±8-OH-DPAT Reduction of AIMs stimulation and at- 1 mg/kg Single dose s.c. 2013 tenuation of striatal glutamate levels 5-HT1A autoreceptor activation and sub- Dyskinesia suppres- Lindenbach ±8-OH-DPAT sequent regulation 1 mg/kg Single dose s.c. sion et al., 2013 of striatal pERK pathway 5-HT1AR activation and subsequent Dose-dependent re- 0.03, 0.1, 0.3 Dupre et al., ±8-OH-DPAT modulation of corti- Single dose i.p. duction of LIDs mg/kg 2008 costriatal glutamate system

Dose-dependent re- Full stimulation of 5- 0.3 and 1 Lindenbach ±8-OH-DPAT Single dose i.p. duction of dyskinesia HT1A receptors mg/kg et al., 2015

5-HT1AR stimulation Intrastriatal or Dupre et al., ±8-OH-DPAT Attenuation of LIDs and subsequent re- 7.5 or 15 mM Single dose s.c. 2011 duction of L-DOPA-

275 EXCLI Journal 2020;19:268-295 – ISSN 1611-2156 Received: January 03, 2020, accepted: February 24, 2020, published: March 02, 2020

Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference induced striatal glu- tamate efflux

Activation of 5-HT1A somatodendritic autoreceptors on raphestriatal neu- rons and subse- quent decrease in Dose-dependent re- the pulsatile 0.1 and 1.0 Dupre et al., ±8-OH-DPAT Eight days i.p. duction of AIMs activation of DA re- mg/kg 2007 ceptors in the stria- tum and prolonga- tion of DA half-life by modulation of raphestriatal- derived DA Being a Sigma-1 re- ceptor antagonist, the effects seen Dose-dependent re- Every 3–4 days here are likely due 5, 10, or 20 Bhide et al., BMY-14802 duction of axial, limb, but for unde- i.p. to activation of 5- mg/kg 2013 and orolingual AIMs fined times HT1AR, as their blockade reverses the observed effects AIM-suppressing ef- Paquette et BMY-14802 Suppression of AIMs fects via a 5-HT1AR 15 mg/kg Single dose i.p. al., 2009 agonist mechanism Stimulation of the 5- Effective attenuation HT1AR and reduc- 1 ng, 10 ng, Intra-subtha- Marin et al., of all LIDs at higher tion of the activity of Single dose or 1 μg lamic nucleus 2009 doses the corticostriatal glutamate pathway Reduction of L- 5-HT1A autoreceptor Bibbiani et Sarizotan DOPA-induced dyski- mediated mecha- 2.5 mg/kg Single dose Oral al., 2001 nesias nisms

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Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference Prominent 5-HT1AR- Dose-dependent re- Gerlach et Sarizotan mediated mecha- 1 or 5 mg/kg Single dose i.p. duction of AIMs al., 2011a nism of action

Fenfluramine Stimulation of 5- 0.25 or 2.5 (FEN) HT1AR because its mg/kg Reduction of AIMs Bishop et al., antagonism re- Three doses i.p. 3,4-methylenedi- occurs in either case 2006 verses the effects of 0.25 or 2.5 oxymethamphet- MDMA and FEN mg/kg amine (MDMA) Dextrome- Indirect stimulation Paquette et Suppression of AIMs 45 mg/kg Single dose i.p. thorphan of 5-HT1AR al., 2012 Decrease in the peak in DA levels (presumably re- NLX-112 (befir- Reversion of L- Iderberg et leased by sero- 0.16 mg/kg Single dose i.p. adol or F13640) DOPA-induced AIMs al., 2015b tonergic neurons) by modulation of 5- HT1AR Significant inhibition of striatal serotonin Acute: Single release and damp- Reversion of L- 0.04 and dose McCreary et NLX-112 ening L-DOPA-me- i.p. DOPA-induced AIMs 0.16 mg/kg Chronic: 2 al., 2016 diated increases in weeks dopamine and stria- tal GABA levels AIM-suppressing ef- 1, 4, or 10 Paquette et Buspirone Suppression of AIMs fects via a 5-HT1AR Single dose i.p. mg/kg al., 2009 agonist mechanism Dose-dependent re- Due to action at the 1 or 2.5 Eskow et al., Buspirone Two weeks i.p. duction of LIDs 5-HT1AR mg/kg 2007 Dose-dependent re- Partial stimulation of 1 and 3 Lindenbach Buspirone Single dose i.p. duction of dyskinesia 5-HT1AR mg/kg et al., 2015 Dose-dependent at- tenuation of the in- Possible activation 2.5, 5 and 10 Gerlach et Buspirone Single dose i.p. creased of 5-HT1AR mg/kg al., 2011b contraversive circling

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Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference which is an animal model of LIDs Dose-dependent re- 0, 2 or 10 intra-striatal F13714 duction of AIMs μg/side s.c. Dose-dependent re- Activation of striatal intra-striatal Meadows et duction of AIMs 5-HT1A hetero-re- Single dose 0, 10 or 30 al., 2017 F15599 ceptors Significant reduction μg/side of LIDs at the highest s.c. dose Activation of pre- 0.02-0.04 F13714 synaptic 5-HT1A au- mg/kg Improvement of L- toreceptors DOPA-induced LIDs Activation of cortical Iderberg et F15599 postsynaptic 5-HT1A 0.16 mg/kg Single dose i.p. al., 2015a heteroreceptors Activation of all 5- Modest attenuation 0.16-2.5 HT1AR subpopula- of peak LIDs severity mg/kg tions Reduction of the ex- cessive swings in L- Reduction of L- 0.018 and (SUN DOPA-derived do- Tani et al., DOPA-induced fore- 0.036 3 to 4 weeks s.c. N4057) pamine release 2010 limb hyperkinesia mg/kg/h from the striatal ser- otonergic terminal Possibly through Serotonin- modulation of norepinephrine Enhancement of L- 10 mg/kg/ Nishijima et serotonin- Five days i.p. reuptake inhibitors DOPA-induced AIMs day al., 2016 norepinephrine (SNRIs) reuptake Inhibition of the ef- flux of L-DOPA-de- Selective serotonin Suppression of L- rived DA via 5- Inden et al., reuptake inhibitors DOPA-induced rota- 10 mg/kg Single dose i.p. HT1AR and modula- 2012 (SSRIs) tional behavior tion of D1 receptors signaling

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Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference Modulation of 5- HT1AR and reduc- Fluoxetine significant reduction tion of dopamine Nevalainen et 10 mg/kg Single dose i.p. of AIMs scores and 5-HT release al., 2014 from the 5-HT nerve fibers A significant reduc- Acute: 5 or Single dose tion of LIDs in both 10 mg/kg acute and chronic in- jections, however, Serotonin trans- Fidalgo et al., i.p. with a significant re- porter blockade Chronic: 10 2015 18 days duction of the thera- mg/kg peutic of L- DOPA Enhancing endoge- Dose-dependent re- nous 5-HT, and 2 and 5 Lindenbach Citalopram Single dose i.p. duction of dyskinesia stimulation of 5- mg/kg et al., 2015 HT1A/1BR Significant effects Alleviation of LIDs in on the expression of Kuan et al., Citalopram 40 mg/kg/day Nine weeks Oral rodent 5HT1BRs in the stri- 2008 atum Anti-dyskinetic im- 0, 3, or 5 Citalopram pacts are partially Attenuation of AIMs mg/kg reversed with expression without Conti et al., WAY100635 use Three weeks s.c. interfering with motor 2014 suggesting the 0, 0.5, or performance involvement of the 1.25 mg/kg 5-HT1AR

Escalated raphe 5- 5, 10 and 20 Fluoxetine HT levels and re- mg/kg duced 5-HT turno- Dose-dependent re- Bishop et al., ver proximal to dor- Single dose Citalopram duction of AIMs 3 or 5 mg/kg i.p. 2012 sal raphe neurons

and subsequent 0.3, 0.5 and Paroxetine stimulation of local 1.25 mg/kg

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Category Treatment Effect(s) Mechanism(s) Dose Duration Route Reference 5-HT1A autorecep- tors

Clomipramine TCAs with higher af- Serotonine block- finity for serotonin ade may increase Tricyclic antidepres- blockade (clomipra- 5-HT stimulation of 7.5, 15 and Conti et al., Single dose i.p. sants (TCA) mine) render the 5-HT1A autorecep- 30 mg/kg 2016 most significant anti- tors to normalize LIDs impacts DA release

Reduction of L- DOPA-induced dyski- 5HT2A/C and D2/3R an- Antagonistic activity Oh et al., nesias when coad- 5 mg/kg Single dose Oral tagonist at 5HT2A/C R 2002 ministered with L-DOPA

No effects on the ap- 0.01, 0.1 or Taylor et al., 5-HT2AR antagonists M100907 pearance or intensity - Single dose i.p. 1.0 mg/kg 2006 of AIMs

DA release as a “false transmitter” Serotonin neuron Serotonin neuron A progressive wors- Carlsson et from the graft-de- - - - transplant transplants ening of LIDs al., 2007 rived serotonergic terminals NM, not mentioned; LIDs, levodopa-induced dyskinesias; AIMs, abnormal involuntary movements; DA or D, dopamine; 5-HTP, 5-Hydroxytryptophan; ±8-OH- DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; R, receptor; NMDA, N-Methyl-D-aspartic acid; L-DOPA, levodopa; 5-TH, 5-hydroxytryptamine; LTP, long-term potentiation; SPN, spiny projection neuron; GABA, gamma-Aminobutyric acid

Table 2: Quality check of the included publications based on modified CAMARADES’ animal study quality checklist Criterion Publication in a Randomiza- Allocation Blinded as- Statement of Sample- Statement of Statement re- peer-reviewed tion to conceal- sessment inclusion and size compliance with garding pos- journal treatment or ment of outcome exclusion of calcula- regulatory re- sible conflict control animals tion quirements of interest Scores 49 16 21 31 26 0 49 20

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Dual D1/2 and 5-HT1AR agonist L-DOPA-derived DA to vesicles in the sero- tonergic neurons and improved LIDs. Also, l-Stepholidine (l-SPD) Mo et al. found that both acute and the stimulation of these receptors decreased chronic administration of l-SPD reduced limb glutamate and gamma-Aminobutyric acid and axial dyskinesias in PD rats. Also, the (GABA) release in the striatum reducing the study found that injection of WAY100635 (it severity of LIDs (Tronci et al., 2013). In an- should be noted that WAY100635 is not a se- other study performed by the same authors, the same results were achieved in both acute lective 5-HT1A antagonist so the results as a and chronic treatment groups (Tronci et al., "proof" of 5-HT1A mechanism should be treated with caution) reversed the therapeutic 2015). effects of l-SPD, indicating the key role of 5- Eltoprazine HT1AR in its antidyskinetic effects. However, Six citations assessed the effects of el- it should be noted that WAY100635 is not a toprazine on LIDs. All of these studies selective 5-HT1A antagonist but is also a D4 showed that eltoprazine dose-dependently re- ligand, so all results from studies using this duced LIDs, or abnormal involuntary move- molecule as a "proof" of 5-HT1A mechanism ments (AIMs) both in acute and chronic injec- should be treated with caution. Mo et al. also tions (Bezard et al., 2013b; Ghiglieri et al., revealed that l-SPD increased the expression 2016; Paolone et al., 2015; Pinna et al., 2016; level of 5-HT1AR mRNA in the lesioned stri- Tronci et al., 2015, 2013). However, one atum (Mo et al., 2010). study showed that these effects were accompanied by a partial worsening of anti- 5-HT1BR agonists PD effects of L-DOPA, which might be a con- We found two articles regarding the cern in this regard (Bezard et al., 2013b). effects of CP94253 on LIDs. It was shown Possible suggested mechanisms for anti-LIDs that CP94253 administration mitigated LIDs effects of eltoprazine are activation of 5- in rats. It was postulated that 5-HT1BR activa- HT1A&BRs, presynaptic reduction of DA tion alleviated LIDs through modulation of release, decrease in serotonin neurons the D1 receptor function (Jaunarajs et al., activity, reestablishment of long-term potent- 2009). However, Inden et al. (2012) found iation (LTP) and synaptic depotentiation in that the single-dose administration of this ag- striatonigral medium-sized GABA spiny onist had no or little effect in this regard. The neurons (the direct pathway) and subsequent difference might result from the route and du- regulation of D1 receptor-dependent cAMP/ ration of agonist injection and the fact that PKA/mGluR1p845 and ERK/mTOR signal- Inden et al. assessed the agonist effects on ro- ing pathways, modulation of NMDA receptor tational behavior and not dyskinesia. subunits i.e. GluN2A/GluN2B, decrease in the glutamate release induced by activation of Mixed 5-HT1A&B R agonists 5-HT1AR located on the corticostriatal terminals, and decrease in the expression of 5-Hydroxytryptophan (5-HTP) zif-268 gene (Bezard et al., 2013b; Conti et Our search yielded two citations that used al., 2016; Ghiglieri et al., 2016; Paolone et al., 5-HTP as a treatment for LIDs. Tronci et al. 2015; Pinna et al., 2016; Tronci et al., 2015, showed that both acute and chronic admin- 2013). Paolone et al., however, argued that 5- istration of 5-HTP in hemiparkinsonian rats HT1A improved the serotonergic tone and decreased Rs-induced decrease in striatal gluta- LIDs. This study also showed that various mate release and not striatal ectopic dopamine doses of 5-HTP had no difference in their release was apparently responsible for the im- anti-LIDs effect. The authors revealed that 5- pacts rendered by eltoprazine (Paolone et al., HTP-derived serotonin activated both sub- 2015) This is somehow in contradiction with the findings of other studies mentioned ear- types of 5-HT1R which led to displacement of lier.

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Recent clinical trials assessed the effects NR2B subunits of NMDA receptors between of eltoprazine in dyskinetic PD patients yield- intra/extra-synaptic parts, and dampening of ing promising results in this regard. Sven- glutamatergic neurons activity which projects ningsson et al. assessed the effects of a single to the striatum from the cortex (Carta et al., oral dose of eltoprazine, at 2.5, 5 and 7.5 mg, 2007; Iderberg et al., 2013; Munoz et al., in 22 patients with PD suffering from LIDs 2009, 2008). and showed that 5 and 7.5 mg doses were well ±8-OH-DPAT tolerated and beneficial for this purpose with- By far, ±8-OH-DPAT is the most com- out compromising normal motor responses to monly-used serotonergic drug whose effects L-DOPA. However, no difference was found on LIDs have been well investigated. We in Unified Parkinson's Disease Rating Scale found eleven citations in this regard all of (UPDRS) part III scores between the placebo which showed that acute (single dose) or and eltoprazine treatments (Svenningsson et chronic administration of ±8-OH-DPAT, al., 2015). Another (please see dose-dependently alleviated LIDs in hemipar- NCT02439125) evaluated the safety, tolera- kinsonian rats (Ba et al., 2007; Bishop et al., bility, and efficacy of three different doses 2009; Dupre et al., 2007, 2008, 2011; Inden et (2.5, 5 and 7.5 mg) of eltoprazine in treating al., 2012; Lindenbach et al., 2013, 2015; LID in 60 PD participants; however, its re- Nahimi et al., 2012; Tomiyama et al., 2005). sults have not been yet published. Tomiyama et al. found that chronic ad- Anpirtoline ministration of ±8-OH-DPAT reduced the We found a citation that assessed anpirto- number of L-DOPA-induced motor compli- line impacts on LIDs. Bezard et al. showed cations, such as rotational behavior. In this that single-dose anpirtoline injection dose-de- study, it was shown that ±8-OH-DPAT pendently decreased LIDs in hemiparkin- blocked the up-regulation of dynorphin sonian rats. Anpirtoline, as opposed to el- (DYN) mRNA in the lesioned striatum. The toprazine, preferentially activates 5-HT1BR upregulation of DYN mRNA was associated subtype, which is located at serotonergic ter- the motor manifestations of PD, such as dys- minals, and at moderate doses shows better kinesia. This study also found that activation results compared with eltoprazine. These ef- of 5-HT1AR by this agonist decreased the ac- fects are at least due to controlled DA, gluta- tivity of serotonergic neurons in the raphe nu- mate, and GABA release (Bezard et al., cleus and thus modulated L-DOPA metabo- 2013a). lism. The same study also showed that ±8- OH-DPAT injection did not change the Combination of ±8-OH-DPAT mRNA levels of the receptor and did not (1A)/CP-94253 (1B) Four studies proved the synergic effects of cause receptor down-regulation (Tomiyama combined administration of ±8-OH-DPAT et al., 2005). The findings of Ba’s study were (1A)/CP-94253 (1B) on the improvement of consistent with the previous study and proved LIDs in rats. These impacts were shown in that both acute and chronic ±8-OH-DPAT ad- both acute and chronic administration of the ministration improved L-DOPA-induced mo- combination (Carta et al., 2007; Iderberg et tor complications. Ba et al. revealed that al., 2013; Munoz et al., 2009, 2008). It has treatment with ±8-OH-DPAT decreased the been shown that serotonergic neurons play a GluR1 hyperphosphorylation leading to a crucial role in LIDs; as the existence of sero- normalized motor response in L-DOPA- tonin afferent neurons in the nigrostriatal sys- treated animal (Ba et al., 2007). tem is crucial for LIDs (Carta et al., 2007). Similarly, Bishop et al. found that the The suggested mechanisms of action of this improving effects of ±8-OH-DPAT on AIMs 1AR, as the impacts combination are regulation of DA release were mediated via 5-HT were abolished by antagonization of the from serotonergic neurons, rearrangement of receptors using WAY100635. These effects

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were replicated in both systemic and intrastri- BMY-14802 as a promising candidate for fu- atal injection of the agonist and antagonist. ture clinical trials (Paquette et al., 2009). This study also found that treatment with ±8- Sarizotan OH-DPAT decreased c-fos expression and It was found that sarizotan dose-de- changed the transcriptional stimulation of pendently reduced AIMs/LIDs in L-DOPA- neurons in the postsynaptic striatum. Also, the treated rats (Bibbiani et al., 2001; Gerlach et therapeutic course reduced preprodynorphin al., 2011a; Marin et al., 2009). Marin et al. (PPD) mRNA in the striatum which was found that high-dose (10 ng and 1 µg) injec- associated with dyskinetic behavior in PD tion of sarizotan to subthalamic nucleus sig- (Bishop et al., 2009). In studies by Dupre et nificantly reduced the axial, limb, and orolin- al., it was revealed that ±8-OH-DPAT injec- gual dyskinesias score possibly by activation tion alleviated LIDs by decreasing the release of the 5-HT1AR. This study stated that sarizo- of raphe-striatal DA and corticostriatal gluta- tan had no impact on the pharmacokinetics of mate. It also affected postsynaptic factors L-DOPA. Evidence suggests that sarizotan- linked to LIDs such as PPD and glutamic acid mediated stimulation of 5-HT1AR dampens decarboxylase (GAD) mRNA (Dupre et al., the activity of glutamate pathways in the cor- 2007, 2008, 2011; Lindenbach et al., 2013). tex. It also modulates the activity of postsyn- Lindenbach et al. showed that ±8-OH-DPAT aptic DA receptors such as D3 and decreases treatment bidirectionally modulated pERK the pulsatile activation of DA receptors in the expression via stimulation of 5-HT1A Rs, de- striatum, all of which reduce the severity of creases D1R supersensitivity and thus im- L-DOPA-induced AIMs (Bibbiani et al., proved LIDs (Lindenbach et al., 2013). How- 2001; Gerlach et al., 2011a; Marin et al., ever, these authors showed that 5-HT syn- 2009). This all can happen in STN as a glu- drome was a major concern in this regard and tamatergic nucleus of the basal ganglia should be taken into account in future studies (Marin et al., 2009). involving 8-OH-DPAT (Lindenbach et al., Clinical trials that have used sarizotan as 2015). In a positron emission tomography a treatment for LIDs in PD patients have (PET) study by Nahimi et al., it was revealed yielded inconsistent results until now. In a that ±8-OH-DPAT injection prevented the ac- phase II clinical trial (SPLENDID study), cumulation of DA in the lesioned striatum and Olanow et al. found that treatment with sari- reduced the displacement of DA receptor ra- zotan (2-10 mg) caused a remarkable decrease dioligand and LIDs in L-DOPA-treated rat in dyskinesia and predominantly its trouble- (Nahimi et al., 2012). some form. This was manifested by improve- BMY-14802 ments in home diary measures of dyskinesia, Our search yielded two results that as- UPDRS, and clinical global impression sessed the effects of BMY-14802 on LIDs or measures determined by both patients and in- AIMs. Both studies showed that single and vestigators. No change was detected in OFF multiple-dose administration of BMY-14802 time in this study. Unfortunately, worsening in hemiparkinsonian rats reduced the severity of Parkinsonism was seen in a number of pa- of LIDs/AIMs (Bhide et al., 2013; Paquette et tients leading to medication discontinuation al., 2009). Bhide et al. found that BMY-14802 (Olanow et al., 2004). Afterwards, in a dou- administration dose-dependently decreased ble-blind, randomized, multinational, Phase orolingual, axial, and limb AIMs, which were III study (PADDY-II), the efficacy and safety abolished upon injection of WAY100635. of sarizotan in PD patients were established This suggested the role of 5-HT1AR in this re- (Müller et al., 2006). Accordingly, because gard. Interestingly, this agonist did not change sarizotan missed Phase III efficacy endpoints L-DOPA therapeutic efficacy in PD (Bhide et in PADDY-1/2 trials, its further investigation al., 2013). In another study, Paquette et al. was discontinued. Others found that sarizotan achieved the same results and suggested at 2 mg/kg/day dose improved UPDRS and

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was safe in PD patients with dyskinesia, how- including axial, limb, and orolingual dyskine- ever, no significant improvements happened sias (Iderberg et al., 2015b; McCreary et al., compared to placebo on any diary-based 2016). Iderberg’s study showed that the ob- measure of dyskinesia or the AIMS score in served effects disappeared by antagonization the sarizotan group (Goetz et al., 2007). of 5-HT1AR by WAY100635. This study as- sumed that the anti-dyskinetic impacts of (FEN) and 3,4-methylenediox- NLX-112 might be mediated through damp- ymethamphetamine (MDMA) In a study by Bishop et al., the effects of ening 5-HT release and the L-DOPA-induced FEN and MDMA on AIMs in hemiparkin- upsurge of DA. However, this study could not sonian rats were investigated. Both FEN and prove the effects of NLX-112 on striatal glu- MDMA reduced total, axial, and limb AIMs tamate release (Iderberg et al., 2015b). in a dose-dependent manner. However, only McCreary et al. revealed that a 2-week injec- MDMA treatment reduced the severity of oro- tion of NLX-112 reversed AIMs proving that lingual dyskinesia. The reported effects were there is no desensitization to its anti-dyski- netic impacts. This study confirmed the idea abolished upon administration of 5-HT1AR antagonist WAY100635, suggesting a 5- that 5-HT1AR modulation decreased the activ- ity of serotonergic neurons and blocked un- HT1AR-mediated mechanism of action. controlled DA release, i.e., “false neurotrans- Nonetheless, due to the destructive effects of mitter.” In line with the previous study, NLX- MDMA on 5-HT nerve fibres and heart 112 did not affect striatal glutamate release valves, its clinical use in humans is unlikely but decreased the L-DOPA-mediated increase (Bishop et al., 2006). in GABA levels in the striatum (McCreary et Dextromethorphan al., 2016). Paquette et al. found that dextromethor- phan reduced the expression of L-DOPA-in- Buspirone We found four citations that assessed the duced AIMs both in Wistar and Sprague- effects of buspirone on LIDs/AIMs in PD rats. Dawley rats. This effect subsequently All of these studies showed that buspirone reversed by injection of WAY100635, dose-dependently reduced LIDs/AIMs indicating the role of 5-HT1AR in this regard. (Eskow et al., 2007; Gerlach et al., 2011b; However, because WAY100635 is a non-se- Lindenbach et al., 2015; Paquette et al., lective antagonist for -HT1AR, this effect might be mediated through the indirect effects 2009). Lindenbach et al. found that buspirone of dextromethorphan on these receptors. Be- dose-dependently decreased LIDs; however, sides, dextromethorphan is considered to in- its tendency towards causing 5-HT syndrome hibit serotonin uptake and lead to serotonin was lower than that of ±8-OH-DPAT. This study also stated that the frequency of 5-HT overflow, causing activation of 5‐HT1A recep- syndrome induced by buspirone was higher in tors and reduction of LIDs. As stated by the rats than humans (Lindenbach et al., 2015). authors, dextromethorphan may not be the Paquette et al. replicated the same results as right candidate for suppression of LIDs in PD the previous study and suggested the key role patients due to its psychogenic and misuse po- of 5-HT1AR in buspirone-mediated anti-dys- tentials, especially in elderlies (Paquette et al., kinetic effects (Paquette et al., 2009). Eskow 2012). et al. showed that buspirone decreased the se- NLX-112 ( or F13640) verity and development of LIDs and simulta- Two studies explored the impact of NLX- neously enhanced L-DOPA anti-PD efficacy. 112 on LIDs in rats. It was found that both The authors found that these effects disap- acute and chronic administrations of NLX- peared when 5-HT1AR antagonist 112 in hemiparkinsonian rats dose-de- WAY100635 was used indicating its role in pendently reversed L-DOPA-induced AIMs, this regard (Eskow et al., 2007). The same

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findings were reproduced in Gerlach’s study dorsal raphe nucleus (DRN). This modulates (Gerlach et al., 2011b). the ectopic release of false neurotransmitters from the serotonergic neurons of the raphe- Flibanserin In a study by Gerlach et al., the effects of striatal system. This study, however, could flibanserin on LIDs were explored. It was not exclude the effects of F13714 on other ar- found that flibanserin, as a preferential 5- eas of the striatum (Meadows et al., 2017). Iderberg et al. found that L-DOPA-induced HT1A receptor agonist, decreased L-DOPA- sensitized controversies circling (i.e., an ani- AIMs disappeared upon systemic low-dose mal LIDs model) mainly at 10 mg/kg dose in administration of F13714 which were re- PD rats. The effects of buspirone were found versed by WAY100635 injection, indicating to be superior to those of flibanserin (Gerlach the exclusive role of 5-HT1AR in this regard. et al., 2011b). This study also showed that the F13714 ad- ministration had no effect on the cortical lev- F15599 els of glutamate, and thus its central mecha- As a G-protein biased agonist, F15599 nism of action depended on the modulation of was applied in 2 citations to alleviate LIDs serotonergic but not the glutamatergic system (Iderberg et al., 2015a; Meadows et al., 2017). (Iderberg et al., 2015a). Meadows et al. found that systemic injection of F15599 significantly decreased AIMs only Tandospirone at higher doses. However, all intra-striatally A study by Iderberg et al. showed that tan- administered doses of F15599 dose-de- dospirone abolished LIDs at higher doses, and pendently reduced AIMs. It was suggested the impact was blocked by the injection of WAY100635, proving the 5-HT1AR-mediated that F15599 modulated 5-HT1A hetero-recep- tors of the forebrain. F15599 renders “biased” mechanism of action. This study also found stimulation of different subpopulations of 5- that tandospirone did not affect the anti-PD effects of L-DOPA. However, the general HT1A heteroreceptors in the striatum, and thus anti-LIDs activity of tandospirone was found it is called biased agonist (Meadows et al., to be lower than that of F15599 and F13714 2017). Iderberg et al. found that F15599 at its due to its partial agonist impacts at 5-HT1A highest dose decreased total AIMs by 80 % R and peak AIMs by 95 %. The study showed (Iderberg et al., 2015a). that these effects were abolished by A clinical trial by Kannari et al. showed antagonization via WAY100635, indicating that administration of tandospirone (15-60 the role of pre- and post-synaptic cortical 5- mg/day) in PD patients improved LIDs in more than 50 % of them, but worsened par- HT1A heteroreceptors in this regard. Iderberg kinsonian features (Kannari et al., 2002). et al. also showed that F15599 did not affect the anti-akinetic impacts of L-DOPA. They Piclozan (SUN N4057) also found that upon stimulation of 5-HT1A Tani et al. investigated the effects of the activity of serotonergic neurons and stria- piclozan on L-DOPA-induced forelimb dys- tal serotonin levels transiently diminished kinesias and showed that piclozan chronic leading to decreased AIMs (Iderberg et al., systemic injection significantly reduced their 2015a). expression. This might be due to a decrease in the excessive L-DOPA-derived DA release F13714 Two citations evaluated the effects of from serotonergic neurons of DRN (Tani et F13714 on LIDs. Meadows et al. showed that al., 2010). both intra-striatal and systemic injection of F13714 dose-dependently reduced LIDs in PD rats. As a biased 5-HT1AR agonist, F13714 preferentially activates the pre-syn- aptic somatodendritic auto-receptors in the

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Serotonin-norepinephrine reuptake HT tone proximal to DRN, which led to the inhibitors (SNRI) activation of regional 5-HT1A autoreceptors and subsequent decrease in LIDs (Bishop et Duloxetine Nishijima et al. found that systemic ad- al., 2012). ministration of duloxetine significantly en- Citalopram hanced L-DOPA-mediated AIMs. The study The impacts of citalopram on LIDs were showed that duloxetine exacerbated AIMs assessed across five studies (Bishop et al., through inhibition of serotonin transporters. 2012; Conti et al., 2014; Fidalgo et al., 2015; Maintenance of DA in the lesioned striatum Kuan et al., 2008; Lindenbach et al., 2015). was also a mentioned mechanism in this re- Bishop et al. found that citalopram improved gard (Nishijima et al., 2016). LIDs via the mechanisms mentioned under fluoxetine. These effects were dose-depend- Selective serotonin reuptake inhibitors ent and did not interfere with the therapeutic (SSRIs) impacts of L-DOPA (Bishop et al., 2012). Dose-dependent reduction of AIMs by injec- Fluoxetine Three studies assessed the effects of tion of citalopram was also seen in Linden- fluoxetine on LIDs or L-DOPA-mediated bach’s study. This might be due to the activa- AIMs/rotational behavior (Bishop et al., tion of 5-HT1AR and also 5-HT1BR, and an in- 2012; Inden et al., 2012; Nevalainen et al., crease in the 5-HT tone. The study also found 2014). Inden et al. revealed that acute sys- that citalopram did not cause significant 5-HT temic injection of fluoxetine significantly re- syndrome compared to the vehicle group as duced the expression of rotational behavior, opposed to buspirone or ±8-OH-DPAT. The which has the same mechanisms as LIDs. The authors concluded that potent 5-HT1AR ago- mentioned effect was abolished by the nists such as ±8-OH-DPAT were less favora- administration of WAY 100135. Inden et al. ble in the treatment of LIDs in PD patients as argued that anti-LIDs effect of fluoxetine they improved LIDs at the cost of inducing 5- HT syndrome (Lindenbach et al., 2015). Fi- might be due to its indirect effects of 5-HT1AR dalgo et al. demonstrated that both acute and and subsequent efflux of L-DOPA-derived chronic administration of citalopram in hemi- DA. parkinsonian rats exerted near-complete sup- Further, fluoxetine reversed the L-DOPA- pression of LIDs. It was found that SSRIs in- mediated increase in ERK1/2 phosphoryla- cluding citalopram increased the synaptic tion (Inden et al., 2012). Nevalainen et al. concentration of serotonergic neurons and found that fluoxetine co-administration with thus stimulated serotonin auto-receptors and L-DOPA significantly reduced AIMs score to modulated LIDs presentation (Fidalgo et al., the baseline in the hemiparkinsonian rats, 2015). In a study by Conti et al. the same re- probably through affecting 5-HT1AR. Accord- sults were achieved. This study also found ingly, WAY 100635 reversed the impacts of that co-administration of citalopram with L- fluoxetine in the same animals. The study DOPA prevented the development of LIDs postulated that fluoxetine modulated postsyn- without affecting its therapeutic efficacy. The aptic cortical 5-HT1AR which controls glu- study proposed that citalopram increased the tamatergic neurotransmission to the striatum synaptic levels of 5-HT and indirectly stimu- and alleviates LIDs (Nevalainen et al., 2014). lated 5-HT1A Another study by Bishop et al. showed that somatodendritic autoreceptors acute injection of fluoxetine reduced AIMs in in DRN which subsequently regulated striatal L-DOPA-treated hemiparkinsonian rats with- DA release and attenuated AIMs. The possi- out affecting its therapeutic efficacy. The au- ble involvement of 5-HT1BR cannot be ex- thors suggested that SSRIs treatment de- cluded though (Conti et al., 2014). Kuan et al. creased the turnover of 5-HT and enhanced 5- showed that chronic treatment with cital- opram was partially able to abolish LIDs in 6-

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OHDA-lesioned rats. This was found to be Tricyclic antidepressants (TCAs) mediated through the complete abolishment In a study by Conti et al., the effects of of the expression of 5HT1B in the striatum in three different TCAs, i.e. desipramine, clom- rats showing LIDs (Kuan et al., 2008). ipramine, and amitryptiline on LIDs were in- Although the preclinical studies have vestigated. It was revealed that been yielded promising results, a clinical trial dose-dependently decreased L-DOPA-in- failed to reproduce the improving effects of duced AIMs. However, the highest dose of citalopram on LIDs in PD patients, which are amitriptyline had a non-significant decreasing seen in animal studies (Korsgaard et al., impact on LIDs. Also, desipramine delayed 1986). The translational failure should be and did not reduce LIDs in hemiparkinsonian addressed in future studies. rats without any change in its efficacy. This study concluded that TCAs with the highest Paroxetine affinity for serotonin blockade, i.e., clomipra- The administration of paroxetine im- mine are the best options in the treatment of proved LIDs in hemiparkinsonian rats in two LIDs. The increase in 5-HT tone and subse- studies (Bishop et al., 2012; Conti et al., quent activation of 5-HT1A 2014). Conti et al. found that prolonged injec- autoreceptors and tion of paroxetine improved LIDs and pre- normalization of DA release were found to be vented their development in rats, and the ef- responsible for the effects seen in this study fects persisted throughout the treatment (Conti et al., 2016). course. The effects were antagonized by the administration of WAY100635, indicating 5-HT2A/CR antagonist the 5-HT1RR-mediated mechanism of action Quetiapine (Conti et al., 2014). Bishop et al. proved that A study by Oh et al. found that chronic paroxetine dose-dependently reduced orolin- quetiapine administration reduced LIDs in gual, axial, and limb AIMs in the rat. This rats. It was proposed that quetiapine indirectly study also found that paroxetine did not decreased serotonin release from the presyn- change L-DOPA efficacy (Bishop et al., aptic terminals in the striatum, which led to a 2012). decrease in the activation of postsynaptic A rather recent clinical trial failed to show 5HT2A/CR (Oh et al., 2002). the improving effects of a 14-day course of paroxetine on LIDs in PD patients, casting 5-HT2AR antagonist doubt on the aforementioned positive effects M100907 seen in animal studies (Chung et al., 2005). It Taylor et al. assessed the impacts of is confusing that several positive results have M100907 on LIDs in 6-OHDA-lesioned rats. been obtained in the rat but not in the clinic, The study found that acute systemic admin- where SSRIs have been rather ineffective in istration of various doses of M100907 re- treating LIDs. As it has been stated by duced the appearance and intensity of D1-in- Korsgaard et., it may have some potential ex- duced dyskinesia, but not L-DOPA-induced planations; first, the dose used in human stud- limb, orolingual, or axial dyskinesia in rats. ies may not be sufficient to produce anti-LID This implies that 5-HT2A antagonism, at least effects. Second, SSRIs might be able to regu- using this medication, may not be a promising late dopamine levels in the CNS if its turnover strategy, based on rat studies (Taylor et al., is higher than the resting state, and third, 2006). However, later studies on MPTP mon- SSRIs might play a nonsignificant role in the keys using EMD-281014, a potent and highly extrapyramidal syndromes (Korsgaard et al., selective 5-HT2A antagonist, proved that 5- 1986). HT2AR antagonism might reduce LIDs with- out compromising the therapeutic effects of L-DOPA (Hamadjida et al., 2018).

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Serotonin neuron transplant the striatum, manifesting as LIDs (Figure 2) Carlsson et al. showed that serotonin neu- (Mahmoudi et al., 2011). ron transplant deteriorated LIDs in rats. It was However, chronic L-DOPA treatment de- found that in the lesioned striatum DA release creases striatal 5-HT nerve fiber density in the from serotonergic neurons terminals as a false absence of neurons neurotransmitter produced swings in the lev- (Nevalainen et al., 2014). Indeed, long-term els of extracellular DA after systemic L- L-DOPA exposure may exert toxic effects DOPA injection and caused LIDs. This study (such as the production of 6-OHDA) on sero- further confirmed the role of serotonin neu- tonergic cells after its uptake, leading to re- rons in the pathophysiology of LIDs duction in 5-HT concentration in striatal and (Carlsson et al., 2007). extrastriatal areas, further deteriorating dyski- nesia in PD patients treated with L-DOPA (Borah and Mohanakumar, 2012; Eskow DISCUSSION Jaunarajs et al., 2012). L-DOPA treatment, in Serotonergic system modulation holds the long run, may also increase homocysteine promise for the treatment of LIDs levels causing oxidative stress and excitotox- Oral L-DOPA is the mainstay of treatment icity. Activation of these aberrant pathways for PD patients; however, chronic exposure to destructs serotonergic neurons leading to re- the medication results in the development of duced 5-HT levels and 5-HT1AR supersensi- AIMs in most of these patients, which are tivity after L-DOPA treatment. Upon a de- known as LIDs. However, the mechanisms creased serotonergic activity, dopamine con- are not elucidated (Politis et al., 2014). Evi- centration decreases in several brain regions dence suggests that PD patients suffering innervated by 5-HT neurons (Lundblad et al., from LIDs have a more substantial, but a 2009; Müller, 2002; Navailles et al., 2011). briefer escalation in DA levels in the striatum All these mechanisms would be finally en- than those with more stable responses (stable sued by the deterioration of LIDs, indicating responders) (de la Fuente-Fernandez et al., the vital role of the serotonergic system in the 2004). pathogenesis of dyskinesia. Studies have established that the integrity Mechanisms by which modulation of of serotonergic neurons is a critical factor in serotonergic neurons affect LIDs are but are the development of LIDs, as modulation of not limited to, regulation of DA release from serotonergic projections and their activity us- serotonergic neurons, rearrangement of ing serotonergic receptors agonists result in NR2B subunits of NMDA receptors between LIDs improvement (Cenci, 2014; Politis et intra/extra-synaptic parts, and regulation of al., 2014). Serotonergic neurons, which re- the activity of cortical glutamatergic neurons main intact early in the disease course, take projecting to the striatum (Iderberg et al., part in the transformation of exogenous L- 2013; Munoz et al., 2009, 2008). DOPA to DA, its storage, and release (Carta Also, selective activation of corticostriatal et al., 2007; Tronci and Carta, 2013). The pro- 5-HT1ARs and simultaneously prevention of duced DA is co-stored with serotonin in sero- stimulation of those on thalamocortical and tonergic terminals as a false neurotransmitter raphestriatal synapses (functional and ana- and co-released via a process known as tomical selectiveness) result in first, con- compensatory co-transmission (Mahmoudi et trolled false neurotransmitter (DA) swings in al., 2013). Nonetheless, the lack of autoregu- the serotonergic terminals and second, regul- latory mechanisms existing in dopaminergic ation of corticostriatal glutamatergic trans- neurons such as dopamine transporter (DAT) mission. The reason for the prevention of ac- and D2 inhibitory receptors in serotonergic tivation of 5-HT1ARs on thalamocortical and neurons leads to the aberrant release of DA in

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Figure 2: Normal conditions (1) vs. L-DOPA-induced dyskinesias (LIDs) (2). 1: In normal conditions dopaminergic neurons are responsible for the release of dopamine (DA) in the brain. These cells pos- sess autoregulatory mechanisms such as dopamine transporter (DAT) and D2 inhibitory receptors which prevent upsurges of dopamine in the synaptic space. 2: In pathologic conditions i.e., LIDs, serotonergic neurons, which remain intact early in the disease course, take part in the transformation of exogenous L-DOPA to DA, its storage, and release. The produced DA is co-stored with serotonin in serotonergic terminals as a false neurotransmitter and co-released via a process known as compensatory co-trans- mission. Nonetheless, the lack of autoregulatory mechanisms existing in dopaminergic neurons such as DAT and D2 inhibitory receptors, in serotonergic neurons leads to the aberrant release of DA in the striatum, manifesting as LIDs. D2R, D2 inhibitory receptors; 5-HT, 5-hydroxytryptamine.

raphestriatal projections resides in the fact activation of those reside in nigrostriatal pro- that their stimulation may curb the therapeutic jections (Huot et al., 2011). efficacy of L-DOPA (Carta et al., 2007, 2008; It is worthy to note that modulation of pre- Huot et al., 2011). This, however, should be synaptic 5-HT1A/1B Rs also ameliorates D1 re- addressed in future studies. ceptor-induced dyskinesia in animal models On the other hand, 5-HT2ARs antagoniza- of PD by attenuation of striatal glutamate lev- tion produces the same effects described els. As augmented striatal dopamine D1 re- above. Again, to exert anti-dyskinetic effects ceptor-induced signaling is involved in LIDS, and simultaneously not compromise L-DOPA its decrease invoked by regulation of sero- efficacy, selective anatomical and functional tonergic system could be considered a vital antagonization seems necessary. This means therapeutic target for LIDs (Dupre et al., that the stimulation of those receptors located 2013; Jaunarajs et al., 2009). in corticostriatal areas and the prevention of

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BENCH TO BEDSIDE TRANSLATION imposes substantial denervation of DA neu- FAILURE rons, which is highly improbable until the end stages of PD. Also, in the studied animal Here, it is noteworthy to mention that al- model, the rodent possesses a rather intact ser- most all serotoninergic compounds tested otonergic system, which is unlikely to be the have been under investigation by giant phar- case in PD patients (Cenci, 2014). Also, dys- maceutical industries, and because their very kinetic animals are reported to have increased first testings in experimental models did not 5-HT nerve fiber density, whereas evidence meet the required endpoints, the industry did suggests that the 5-HT system becomes de- not support their early clinical testing; as re- generated in PD patients. These factors may flected in the few numbers of patients in- also affect the outcome of the experimental cluded in these expensive studies (Olivier, studies and result in a reproducibility crisis. 2015). Third, different ratios of L-DOPA and Several clinical trials have been per- benserazide may have been used in combina- formed on PD patients, aiming at alleviating tion across various studies; the latter is a de- LIDs with 5-HT1ARs agonists such as sarizo- tan. Some of these studies have yielded carboxylase inhibitor that does not cross the promising results (Bara-Jimenez et al., 2005; blood-brain barrier and prevents L-DOPA’s Goetz et al., 2007; Olanow et al., 2004). How- peripheral metabolism. This may affect the ever, others have failed to reproduce the anti- amount of L-DOPA as well as 3-methoxyty- LIDs impacts of these medications or have rosine (3-MT) available in the CNS (at the shown an improvement of LIDs at the cost of same doses of L-DOPA used) (Kent et al., worsening parkinsonism (Chung et al., 2005; 1990). Higher levels of 3-MT are associated Kannari et al., 2002; Korsgaard et al., 1986). with higher levels of LIDs, complicating the This casts doubt over the usefulness of these interpretation of studies results (Lee et al., strategies in PD patients. 2008). The translational failure seen in clinical trials may stem from several facts as follows; CONCERNS OVER SIDE EFFECT first, as emerges from the results of this study, PROFILE the quality of the included articles was only Direct or indirect overactivation of post- modest, highlighting a need for more rigorous synaptic 5-HT1AR in rats and 5-HT1/2AR in design and conducting high-quality experi- humans or blockade of postsynaptic D2 recep- mental studies in this field. It is highly tors results in a phenomenon which is known plausible that taking into account measures as the 5-HT syndrome. Also, the co-admin- like randomization, blinding, monitoring istration of L-DOPA with medications that af- physiological factors, included and excluded fect the serotonin system imposes a high risk animals, allocation concealment, and last but of developing this syndrome. However, this is not least sample size calculation will reduce more like a spectrum as some serotonergic the experimental studies bias and fill the gap agents pose a higher risk for the syndrome between bench and bedside. On the other than others (Lindenbach et al., 2015). Unfor- hand, the flaws of clinical trials should not be tunately, due to the similarity of the symp- overlooked. This can be a low statistical toms between 5-HT syndrome and PD, its di- power of the trial to identify the real benefit agnosis is occasionally cumbersome leading of the treatment under investigation (van der to diagnoses such as worsening of PD (Ener Worp et al., 2010). et al., 2003). The mentioned side effects have Second, the translational failure may also been also reported in treatment with the 5- reside in the fact that the 6-OHDA model of HT1B/D agonist, SKF-99101-H, or by the PD in the rat does not entirely mimic the path- mixed 5-HT1A/5-HT1B agonist, 5-HT2 antago- ophysiology of PD. Acute administration of nist, RU24969 (Paolone et al., 2015). 6-OHDA to induce hemiparkinsonism in rat

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Another concern over the therapeutic use humans compared to other species and, also, of serotonergic agents in LIDs is their ability the greater intricacy of the human disease as to reduce the efficacy of L-DOPA or exacer- opposed to experimental models. As we dis- bate parkinsonism, as it was seen in eltopra- cussed earlier, improving the quality of the zine administration (Bezard et al., 2013b). For experimental studies and conducting well-de- instance, Lindenbach et al. showed that 5‐ signed clinical trials will help fill the bench- HT1A agonists administration changes spon- to-bedside gap. taneous movement patterns and represses the pro‐motor impacts of L‐DOPA to some ex- Conflict of interest tent. Nevertheless, the similarities between 5- The authors declare that they have no con- HT syndrome and PD worsening symptoms flict of interest. make it difficult to ascribe these features to either one of the phenomena (Lindenbach et Acknowledgment al., 2015). So, the use of agents that simulta- This study was supported by a grant from neously reduce LIDs and maintain L-DOPA Research Center for Evidence-Based Medi- efficacy, such as SSRIs, is of high priority. cine, Health Management and Safety Promo- Accordingly, loss of anti-parkinsonian effects tion Research Institute, Tabriz University of has marred the development of 5-HT1A/1B ag- Medical Sciences (Grant no.61131). onists, and here again, the rat has been rela- tively ineffective at uncovering this problem REFERENCES with this category of drugs. This may indicate Ba M, Kong M, Ma G, Yang H, Lu G, Chen S, et al. the narrow therapeutic window of these med- Cellular and behavioral effects of 5-HT1A receptor ag- ications. A new therapeutic avenue has been onist 8-OH-DPAT in a rat model of levodopa-induced brought forward by the introduction of com- motor complications. Brain Res. 2007;1127:177-84. pounds with biased agonistic properties, Bara-Jimenez W, Bibbiani F, Morris MJ, Dimitrova T, which can dampen LIDs and are simultane- Sherzai A, Mouradian MM, et al. Effects of serotonin ously devoid of anti-PD impacts (Huot et al., 5-HT1A agonist in advanced Parkinson's disease. Mov 2017). Disord. 2005;20:932-6. Begley CG, Ioannidis JP. Reproducibility in science: CONCLUSION improving the standard for basic and preclinical re- LIDs are of the troublesome long-term search. Circ Res. 2015;116:116-26. consequences of treatment with L-DOPA in Bezard E, Munoz A, Tronci E, Pioli E Y, Li Q, Porras PD patients. A growing body of evidence G, et al. Anti-dyskinetic effect of anpirtoline in animal shows that the serotonergic system is in- models of L-DOPA-induced dyskinesia. Neurosci Res. volved in the pathophysiology of LIDs. This 2013a;77:242-6. systematic review revealed that serotonergic Bezard E, Tronci E, Pioli EY, Li Q, Porras G, agents including 5-HT1AR agonists, 5-HT2AR Bjorklund A, et al. Study of the antidyskinetic effect of antagonists, SSRIs, SNRIs, etc. improve LIDs eltoprazine in animal models of levodopa-induced dys- in hemiparkinsonian rats with an almost ac- kinesia. Mov Disord. 2013b;28:1088-96. ceptable side effect profile. However, the pos- Bhide N, Lindenbach D, Surrena MA, Goldenberg AA, sibility of the 5-HT syndrome and worsening Bishop C, Berger SP, et al. The effects of BMY-14802 parkinsonism should be taken into account. against L-DOPA- and -induced dys- Even though these agents yield promising re- kinesia in the hemiparkinsonian rat. Psychopharmacol- sults in the laboratory, they have not been that ogy (Berl). 2013;227:533-44. much appealing in the clinic. The dramatic ef- Bibbiani F, Oh JD, Chase TN. Serotonin 5-HT1A ago- fects of these agents observed in animal mod- nist improves motor complications in rodent and pri- els and their negligible impacts in clinical tri- mate parkinsonian models. Neurology. 2001;57:1829- als may be explained by a different role 34. played by the serotonergic system in LIDs in

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