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Method Article

Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease

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DOI:

10.3791/62924

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October 4th, 2021

 ,  ,  , 
1Department of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo

* These authors contributed equally

In This Article

Summary

Rodent models of L-DOPA-induced dyskinesias are invaluable tools to identify therapeutic interventions to attenuate the development or alleviate the manifestations that emerge due to the repeated administration of L-DOPA. This protocol demonstrates how to induce and analyze dyskinetic-like movements in the unilaterally 6-OHDA-lesioned rat model of Parkinson's disease.

Abstract

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.

Introduction

The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) represents the most effective treatment for the motor symptoms of Parkinson's disease (PD)1. L-DOPA therapy may ameliorate motor symptoms associated with PD but loses effectiveness with time. Motor fluctuations such as "wearing-off fluctuation" or "end-of-dose deterioration" manifest clinically as a shortened duration of the effect of single L-DOPA doses2. In other cases, clinical manifestations consist of slow twisting movements and abnormal postures (dystonia)3 and occur when dopamine levels are low (off-period dystonia)4. On the other hand, L-DOPA-induced dyskinesias (LIDs) appear when dopamine levels in the plasma and the brain are high5.

LIDs produce debilitating side effects that include motor complications such as choreiform, dystonic, and ballistic6 movements. Once established, LIDs occur after every L-DOPA administration. Motor complications occur in 40%-50% of PD patients undergoing L-DOPA therapy for 5 years, and the incidence increases over the years7. Although the pathophysiological mechanisms involved in the development of LIDs in PD patients are not yet fully elucidated, the extent of dopaminergic denervation, pulsatile L-DOPA administration, downstream changes in striatal proteins and genes, and abnormalities in non-dopamine transmitter systems are factors that contribute to the development of these unwanted side effects6,8,9,10.

The neurotoxin 6-hydroxydopamine (6-OHDA) is a well-characterized tool to study PD in rodents11,12,13,14. Since 6-OHDA does not cross the blood-brain barrier, it must be injected directly into the nigrostriatal pathway. 6-OHDA-induced dopaminergic depletion is concentration- and site-dependent15. Unilateral administration of 6-OHDA at the medial forebrain bundle (MFB) can produce severe (>90%) nigrostriatal damage in rodents16,17,18,19. Chronic administration of L-DOPA to severe unilaterally 6-OHDA-lesioned rodents causes the appearance of dyskinetic-like movements named abnormal involuntary movements (AIMs). Dyskinetic-like movements in rodents share similar molecular, functional, and pharmacological mechanisms related to LIDs in PD patients5. Therefore, 6-OHDA-lesioned rats20 and mice21 are valuable preclinical models to study LIDs. When treated chronically (7-21 days) with therapeutic doses of L-DOPA (5-20 mg/kg), unilaterally 6-OHDA-lesioned rats and mice show a gradual development of AIMs that affect the forelimb, trunk, and orofacial muscles contralateral to the lesion17,18,19,20,22,23,24. These movements are presented at a time course similar to L-DOPA-induced peak-dose dyskinesias in PD patients25 and are characterized by hyperkinetic movements and dystonia5. AIMs are usually scored based on their severity (e.g., when a specific AIM is present) and amplitude (e.g., characterized by the amplitude of each movement)5,23,25.

6-OHDA-lesioned rodent models of LIDs present face validity (i.e., the model has several characteristics that look like the human condition)5,11,26,27,28. Rodent AIMs, similar to what occurs in PD patients, are seen as hyperkinetic (forelimb and orolingual) and dystonic (axial) movements29 and mimics peak-dose dyskinesia. At the molecular and functional level, rodent models share many pathological characteristics with PD patients5, such as upregulation of FosB/ΔFosB19,26,30,31,32,33 and serotonin transporter (SERT)34,35. Concerning predictive validity, drugs that reduce LIDs in PD patients (e.g., the N-methyl-D-aspartate (NMDA) receptor antagonist amantadine) present antidyskinetic efficacy in the rodent model22,36,37,38,39.

The rodent AIMs rating scale was created based on four AIMs subtypes that include AIMs affecting the head, neck, and trunk (axial AIMs), hyperkinetic forelimb movements (limb AIMs), and dyskinetic-like orolingual movements (orolingual AIMs). Although contralateral rotation (locomotive AIMs) is also present in unilaterally lesioned rodents20,22,23,25,40, it has not been scored as a dyskinetic-like movement since it may not represent a specific measure of LIDs22,37,41.

Here, we will describe how to induce and analyze dyskinetic-like movements (axial, limb, and orolingual AIMs) in the severe (>90%) unilaterally 6-OHDA-lesioned rat model of PD. We organized our protocol based on the previous literature and our laboratory expertise.

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Protocol

All experiments were performed in accordance with The Ethics Committee of the Faculty of Philosophy, Sciences, and Letters of Ribeirão Preto (CEUA/FFCLRP 18.5.35.59.5).

1. 6-OHDA lesion

  1. Use Sprague-Dawley male rats weighing 200-250 g at the beginning of the experiments (6 weeks). House the animals (2-3 per cage) under standard laboratory conditions (12:12 h light/dark cycle, lights on at 06:00 h, temperature-controlled facilities (22-24 °C), with food and water available ad libitum.
    NOTE: A complete description of how to generate severe 6-OHDA-lesioned rats is described elsewhere42.
  2. Appropriately acclimate animals before the beginning of any experimental procedure.
  3. Administer (intraperitoneally, i.p.) the norepinephrine transporter inhibitor imipramine (20 mg/kg, dissolved in 0.9% saline solution) 30 min before surgery.
    NOTE: Imipramine administration will increase 6-OHDA selectivity for dopaminergic neurons.
  4. Administer ketamine/xylazine (70/10 mg/kg) intraperitoneally.
  5. Make sure the animal is deeply anesthetized by the lack of response to toe pinch and positioned in a prone position in the stereotaxic apparatus on the top of a heating pad.
  6. Remove the fur on the head and disinfect the surgical area 3 times, alternating between an iodine-based scrub and alcohol.
  7. Use a scalpel to make an incision (approximately 1 cm) at the region where the microinjection will occur.
  8. Clean the skull region with cotton swabs and ensure the Bregma and Lambda are exposed.
  9. Ensure MFB stereotaxic coordinates are taken from bregma43,44,45: -4.3 mm anterior, 1.6 mm lateral (right side), and 8.3 mm ventral (from the dura mater).
  10. Administer the 6-OHDA at a rate of 0.4 µL/min (10 µg in 4 µL of saline solution containing 0.1% ascorbic acid) unilaterally in the right medial forebrain bundle (MFB) using a 50 µL Hamilton glass syringe.
  11. At the end of the surgery, suture the scalp incision and rehydrate the animal with warm (~37 °C) sterile 0.9% saline solution (~10 mL/kg, s.c.).
  12. Remove the animal from the stereotaxic frame and place it in a warmed recovery cage. Monitor until consciousness is regained.
  13. Assess the effectiveness of the dopaminergic lesion 4 weeks post-lesion using a stepping test46,47.
    ​NOTE: In this test, the akinesia of the forelimb contralateral to the lesion is assessed through the number of adjusting steps with the forepaw contralateral to the lesion. Rats presenting three or fewer adjusting steps with the contralateral forelimb are included in the study as putative severely 6-OHDA-lesioned rats48.

2. L-DOPA chronic treatment

  1. Start the chronic treatment on Monday, 4 weeks post-6-OHDA lesion.
    NOTE: Since AIMs will be videotaped for 3 consecutive days per week (Wednesday, Thursday, and Friday) for 3 weeks, it is recommended to start the treatment on Monday.
  2. Treat the rats with freshly prepared L-DOPA (via subcutaneous (s.c.), 1 mL/kg) plus benserazide hydrochloride (5 mg/kg and 12.5 mg/kg, respectively) for 3 weeks, once daily from Monday to Friday45.
    NOTE: Once established, AIMs will manifest with each administration of L-DOPA. Therefore, L-DOPA administration 2-4 times a week after the 3-week induction period is sufficient to maintain a stable expression of AIMs48.

3. AIMs recording and scoring

  1. Perform experiments between 09:00 h and 17:00 h. Ensure that the investigator is entirely unaware of the rats' identity and pharmacological treatment.
  2. Carefully put the rat inside a transparent cylinder (20 cm diameter x 40 cm tall) and allow it to acclimatize for at least 15 min. Ensure that the floor is covered with the bedding material. Mirrors must be positioned behind the cylinder so the experimenter can observe the animal from all possible angles.
    NOTE: If there is more than one rat per experiment, use a cylinder for each rat. Manipulation of the animals between sessions can interfere with the behavioral analysis.
  3. Position a high-resolution video camera in a way that favors the viewing of axial, limb, and orolingual AIMs. Since rotational behavior is present under these experimental conditions, the mirrors behind the cylinder will allow tracking AIMs at a 360° angle. Use a tripod or fix the camera directly to the bench.
    NOTE: Orolingual AIMs can be challenging to score, especially if there is a high incidence of rotational behavior. Capturing videos with the camera positioned slightly below the plane where the animals are at a 15° angle will help observe this movement subtype.
  4. Gently remove the animal from the cylinder and administer L-DOPA (5 mg/kg combined with 12.5 mg/kg of benserazide, s.c.).
  5. Put the animal back in the cylinder and start a timer to track AIMs after L-DOPA injection. Use a video camera to record AIMs for 180 min after the injection of L-DOPA. Although the analysis can be carried out by direct observation of the animal, offline scoring is preferred.
    NOTE: Ensure the timer is also videotaped so that AIMs can be scored at precise times after L-DOPA administration.
  6. Score AIMs at 30 min intervals up to 180 min post-L-DOPA injection (see Table 1 for definitions) as initially described20,23. Scores must be given over 1-2 min epochs and classified as axial, limb, or orolingual (Figure 1).
  7. Carefully observe each AIM and attribute scores for severity and amplitude. Use Table 1 for instructions. Do not include normal behaviors, such as rearing, sniffing, grooming, and gnawing in the rating. There will be a total of six observation periods (30, 60, 90, 120, 150, and 180 min).
SUBTYPES
Axial: torsion of head, neck, and trunk
Limb: involuntary movements of both distal and proximal forelimb
Orolingual: involuntary movements of the orofacial muscles
SEVERITY
0: Absent
1: Occasional (with interruptions, present in less than half of the observation time)
2: Frequent (with interruptions but present in more than half of the observation time)
3: Continuous but interrupted by external sensory stimuli
4: Continuous and not interrupted by external sensory stimuli
AMPLITUDE
Axial
1: Torsion of head and neck at approximately 30° angle
2: Torsion of head and neck at approximately 30° < angle ≤ 60°
3: Torsion of the head, neck, and upper trunk at approximately 60° < angle ≤ 90°
4: Torsion of head, neck, and trunk at > 90° angle, often causing the rat to lose balance
Limb
1: Small involuntary movements of the distal forelimb
2: Movements of low amplitude causing translocation of both distal and proximal forelimb
3: Involuntary movements of the whole limb, including shoulder muscles
4: Strong limb and shoulder movements, often similar to ballism
Orolingual
1: Small involuntary movements of the orofacial muscles
2: Orofacial movements of high amplitude with tongue protrusion

Table 1: AIMS definition and rating criteria.

Rodent behavioral study; sequence of images showing axial, limb, orolingual movements; analysis setup.
Figure 1: Sequence of photos showing each AIM subtype. (A to A'") Axial AIM showing dystonic-like movements in different angles (A: 30° angle, A': 30° < angle ≤ 60°, A": 60° < angle ≤ 90°, and A'": > 90° angle). (B to B") Limb AIM (black arrows) showing involuntary movements of the distal (B and B') and whole forelimb (including shoulder, B"). (C) Orolingual AIM (red arrow) of high amplitude with tongue protrusion. Please click here to view a larger version of this figure.

4. Data analysis

  1. Compute axial, limb, or orolingual AIMs subtypes by multiplying the severity and amplitude scores for each observation period after L-DOPA administration (i.e., six observation periods) as previously described20. The theoretical maximum score that one animal could accumulate in one testing session is 240 (maximum score per observation period is 40, see Table 1 for details).
  2. Plot AIMs scores for all the six observation periods recorded on Wednesday, Thursday, and Friday over the 3 weeks of chronic L-DOPA administration (Figure 2). AIMs can be summed up to indicate each animal's maximum score on each scoring day (Figure 3) or each week (Figure 4) over the 3 weeks of chronic L-DOPA administration.
  3. Verify if the data has a close-to-normal distribution before selecting the statistical analysis approach.
    NOTE: AIMs rating scales consist of ordinal data and can be analyzed with nonparametric statistics. Parametric tests are widely used when comparing AIMs scores across experimental groups following repeated testing sessions40.

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Results

Although the AIMs patterns observed in rats are simpler and limited compared to those observed in humans and nonhuman primates, this model reproduces both hyperkinetic and dystonic-like movements induced by chronic L-DOPA administration. Here we present data collected from a group (n = 10) of unilaterally 6-OHDA-lesioned rats chronically treated with L-DOPA (5 mg/kg combined with 12.5 mg/kg of benserazide) for 3 weeks (Monday to Friday). Note that the data presented in Figure 2,

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Discussion

This protocol demonstrates how to induce and analyze AIMs in the rat model of PD induced by unilateral microinjection of 6-OHDA in the MFB. Chronic daily administration of low doses of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) produced the development of AIMs over the 3 weeks of treatment. Temporal analysis revealed a significant increase of AIMs, and the peak-dose dyskinesia is observed between 30 and 90 min after L-DOPA administration. AIMs are repetitive and purposeless movements affecting axial, limb,...

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Disclosures

The authors have no conflicts of interest.

Acknowledgements

This work was supported by São Paulo Research Foundation (FAPESP, grant 2017/00003-0). We are grateful for the Coordination for the Improvement of Higher Education Personnel (CAPES). We thank Dr. Anthony R. West, Dr. Heinz Steiner, and Dr. Kuei Y. Tseng for support and mentoring.

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Materials

List of materials used in this article
NameCompanyCatalog NumberComments
6-hydroxydopamine hydrobromideSigma-Aldrich, USAH6507Neurotoxin that produces degeneration of catecholaminergic terminals
Benzerazide hydrochlorideSigmaB7283Peripheral dopa-decarboxylase inhibitor
Camera Bullet IR Turbo HD (HD-TVI)  2.8mm BHIKVISIONDS-2CE16C0T-IRPCamera used to record all behavior
Imipramine hidrochlorideAlfa AesarJ63723Norepinephrine transporter inhibitor (NET) used to protect noradrenergic neurons from 6-OHDA
Ketamine hydrochlorideCeva Animal HealthAnesthesia for surgical intervention
L-3,4-dihydroxyphenylalanine (L-DOPA) methyl ester (hydrochloride)Cayman Chemical Company16149Dopamine precursor
MirrorsUsed to observe the behavior of animals during experiments in all directions
Needles 0.30 x 13 mmPrecisionGlideNeedles used to inject drugs
Sodium chloride (NaCl)SamtecSalt
Syringes 1 ml SterileBD PlastipakSyringes used to inject drugs
Transparent cylindersUsed to record animal behavior during experiments
Xylazine hydrochlorideCeva Animal HealthSedative, analgesic and muscle relaxant for surgical intervention

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6 OHDA Rat ModelAbnormal Involuntary MovementsDopaminergic LesionStereotaxic SurgeryPeak Dose DyskinesiaChronic L DOPA TreatmentStepping TestAntidyskinetic Interventions
Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease
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