Motivational properties of D2 and D3 dopamine receptors agonists and cocaine, but not with D1 dopamine receptors agonist and l -dopa, in bilateral 6-OHDA-lesioned rat

Neuropharmacology 70 (2013) 74e82

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Motivational properties of D2 and D3 dopamine receptors agonists and cocaine, but not with D1 dopamine receptors agonist and L-dopa, in bilateral 6-OHDA-lesioned rat Yildiz Zengin-Toktas a, c, *, Nicolas Authier b, e, Hélène Denizot a, c, Carine Chassain a, d, Aziz Hafidi a, Pierre M. Llorca a, c, Franck Durif a, d a

Clermont Université, Université d’Auvergne, EA 7280, Clermont-Ferrand, France Clermont Université, Université d’Auvergne, INSERM U1107, Clermont-Ferrand, France CHU Clermont-Ferrand, Service de Psychiatrie B, 63000 Clermont-Ferrand, France d CHU Clermont-Ferrand, Service de Neurologie, 63000 Clermont-Ferrand, France e CHU Clermont-Ferrand, Service de Pharmacologie, 63000 Clermont-Ferrand, France b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 August 2012 Received in revised form 17 December 2012 Accepted 31 December 2012

Dopamine dysregulation syndrome in Parkinson’s disease (PD) has been attributed to dopamine replacement therapy (DRT). We hypothesize that DRT can induce a potential rewarding effect in an animal model of PD. Using the conditioned place preference (CPP) paradigm, we investigated the motivational effects of L-dopa, dopamine receptor agonists (DRAs), and cocaine in rat with a bilateral 6-OHDA lesion of the nigrostriatal dopaminergic pathway. In 6-OHDA animals, D1 receptors agonist (SKF81297) revealed significantly a conditioned place aversion (CPA) at 3 mg/kg and 9 mg/kg doses. D2 receptors agonist (bromocriptine) induced both CPP and CPA at 1 mg/kg and 10 mg/kg doses respectively. D3 receptors agonist (PD128907) induced a CPP only at 1 mg/kg, comparable to that of cocaine. Sham animals revealed biphasic CPP curves, with significant dose effect, for the intermediate dose of the 3 DRAs. However, L-dopa induced no significant effect while cocaine induced CPP in both lesioned and sham animals. In conclusion, this study confirms the predominant roles of D2R class, and most specifically D3R subtypes, in rewarding properties of DRT. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Parkinson’s disease Dopamine dysregulation syndrome L-dopa Dopamine receptor agonists Cocaine Conditioned place preference

1. Introduction Parkinson’s disease (PD) is primarily regarded as a disorder of movement associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the ventral midbrain, leading to severe dopamine (DA) depletion in the striatum, which is responsible for the motor symptoms. The current treatment of PD is based on dopamine replacement therapy (DRT) using levodopa (L-dopa) and dopamine receptor agonists (DRAs) (Hoehn, 1992). While DRT acts positively in partially restoring the motor deficits elicited by PD, a constellation of addictive syndromes has been noticed in certain patients: addiction to medications, compulsive * Corresponding author. Université d’Auvergne, Faculté de Médecine e Laboratoire EA 7280, 28 Place Henri-Dunant, BP 38, 63001 Clermont-Ferrand Cedex 1, France. Tel.: þ33 6 47 91 34 96. E-mail address: [email protected] (Y. Zengin-Toktas). 0028-3908/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuropharm.2012.12.011

behaviors, and behavioral addictions (Weintraub et al., 2010). These behavioral changes have been called dopamine dysregulation syndrome (DDS) (Lawrence et al., 2003; Pezzella et al., 2005). It is a neuropsychiatric behavioral syndrome associated with substance misuse and behavioral disturbances that can resemble a hypomania state or disturbances in the impulse control system resulting in an uncontrolled urge or drive to perform certain acts (Merims and Giladi, 2008). Compulsive DRT use is not limited to L-dopa, and may occur with all forms of DRT e DRAs with a higher affinity for D2R/D3R than the D1R (Lawrence et al., 2003). However, many case reports highlight the use of acute “rescue” drugs, such as dispersible oral formulations of L-dopa and subcutaneous apomorphine. The addition of intermittent apomorphine injections to the therapeutic regimen can unmask or trigger overuse of DRT (Courty et al., 1997; Giovannoni et al., 2000). Compulsive use of DRAs (other than apomorphine) can occur, which is usually, although not exclusively, associated with the compulsive use of L-dopa. Interestingly,

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behaviors of patients using DRT compulsively are close to those observed after excessive use of psychomotor stimulants such as amphetamines and cocaine (Wise and Bozarth, 1987; Lawrence et al., 2003; Evans and Lees, 2004; Witjas et al., 2005). If DA cell loss in PD mainly involves nigrostriatal projections and is responsible for the motor symptoms of the disease, cell loss from the ventral tegmental area (VTA) was also observed, although to a lesser degree. The cells of the VTA project most prominently into the nucleus accumbens (NAc), olfactory tubercle but also innervate the septum, amygdala and hippocampus. This subset of projections is known as the mesolimbic DA system. Cells in the medial VTA project to the prefrontal, cingulate and perirhinal cortex (Wise, 2004). There is considerable overlap between the VTA cells that project to these various targets. Because of the overlap between the mesocortical and mesolimbic DA neurons, the two systems are often collectively referred to as the mesocorticolimbic system (Wise, 2004). These DA systems are involved in emotion-based behavior including motivation and reward. In PD the mesolimbic and mesocortical projections could be involved in behavioral disorders such as apathy (Thobois et al., 2010). Therefore, the disruption of nigrostriatal, mesolimbic, and mesocortical DA transmission, and DRT, is believed to produce not only effects related to motor functions, but also side effects influencing affectiveeimpulsive components of behavior. In fact, after Ldopa administration when deterioration of DA neurons is mild, DA release may be regulated by the capacity of the DA neuron itself to DA storage and uptake (Kondo, 2008). However, under excessive doses of L-dopa or in advanced stages of the disease, DA is not stored in DA neurons or terminals. Thus, administration of large doses of L-dopa may expose dopamine receptors (DARs) to intermittent or pulsatile high concentrations of DA (Kondo, 2008). On the other hand, DRAs have a long plasma half-life compared to Ldopa and have potent D3 agonistic action, which is thought to be one of the causes of DDS, because D3R is densely distributed in the mesolimbic system of the brain (Suzuki et al., 1998). Furthermore, high doses of DRAs continuously occupy the DARs in all their areas of distribution and could also induce an abnormal overstimulation of DARs. Excessive DA stimulation or continuous stimulation of specific DARs could induce a change in the plasticity of the basal ganglia and thus lead to behavioral disorders. In this study, arguing that DDS in PD can be related to DRT, we hypothesize that L-dopa and DRAs, i.e. D1 receptors (SKF81297), D2 receptors (Bromocriptine) and D3 receptors (PD128907) at three different doses, can induce a potential rewarding effect using the conditioned place preference (CPP) test in an animal model of PD with a bilateral lesion of the nigrostriatal DA pathways. Cocaine, for which the rewarding effects are well established, was used to validate our procedure for the CPP test and results obtained for 6OHDA lesioned rats were compared to these obtained for sham animals. 2. Materials and methods 2.1. Animals We obtained 261 adult male Sprague-Dawley rats (180e210 g) from Charles River (L’Arbresle, France) and maintained them in a controlled environment (lights on 07:00e19:00, 22  C) with food and water freely available. They were housed 3e4 per cage. The experiments followed the ethical guidelines of the International Association for the Study of Pain and the European Community Council directive of 24 November 1986 (86/609/EEC) and that of the Animal Ethics Committee of the Clermont University. All efforts were made to minimize animal suffering, to reduce the number of animals used. 2.2. Surgery We chose the rat model with bilateral lesions of the nigro-striatal DA pathway (Paillé et al., 2007). Anesthesia was given with Ketamine 60 mg/kg, i.p. and

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RompunÒ (xylazine, 10 mg/kg, i.p.). Animals were placed in a stereotaxic frame (David Kopf Instrument, CA, USA). 149 rats were injected bilaterally in the medial forebrain bundle (MFB) with 6-hydroxydopamine (6-OHDA, Sigma-Aldrich, France) (0.5 mL/min) after dissolution in a vehicle solution (0.02% ascorbate saline) at a concentration of 1.5 mg/mL. 6-OHDA was injected bilaterally in two deposits (2.25 and 2.85 mg, respectively) at the following coordinates (in mm relative to bregma and the surface of the dura mater): anterior (A) 4.0; lateral (L)  0.8; ventral (V) 8.0; tooth bar at þ3.4 and A 4.4; L 1.2; V 7.8; tooth bar at 2.4. In order to preserve adrenergic neurons from 6-OHDA toxicity, animals received desipramine (25 mg/kg, i.p., Sigma-Aldrich, France) 30 min prior to the toxin injection (Pioli et al., 2008); 112 sham-lesioned rats received only the vehicle at the same coordinates.

2.3. Drugs Doses (mg/kg), route of administration and waiting time before being tested in our experiments of drugs were as follow: L-dopa (L-3,4-Dihydroxyphenylalanine methyl ester hydrochloride, Sigma-Aldrich, France) [50-100-200] þ Benserazide (Benserazide hydrochloride, Sigma-Aldrich, France), 25% of L-dopa, i.p., 10 min and was dissolved in NaCl 0.9% solution; Cocaine (Euromedex, France), [10], i.p., immediately before assessment and was dissolved in NaCl 0.9% solution; D1 receptors agonist (()-SKF81297 hydrobromide, Sigma-Aldrich, France), [1-3-9], i.p., 15 min and was suspended in Tween 80 and NaCl 0.9% solution; D2 receptors agonist ((þ)-Bromocriptine methanesulfonate salt, Sigma-Aldrich, France), [0.1-1-10], i.p., 60 min and was suspended in Tween 80 and NaCl 0.9% solution; and D3 receptors agonist ((þ)-PD 128907 hydrochloride, Sigma-Aldrich, France), [0.3-1-3], s.c., 30 min and was dissolved in NaCl 0.9% solution.

2.4. Conditioned place preference test 2.4.1. Apparatus CPP experiments were performed in three identical boxes (Imetronic, Pessac, France) formed by two lateral chambers (15  15  20 cm) connected by a central alley (5  15  20 cm) (middle neutral compartment). Two sliding doors separated the alley from the chambers. In each chamber two Plexiglas prisms with triangular bases (5  7  19 cm) were arranged to form different patterns (always covering the same surface of the chamber) and were used as conditioned stimuli. Two different metallic grids, one with large (1 cm) squares and the other with small (0.5 cm) circles were also used as conditioned stimuli. Two infrared photocells were present in each compartment and detected the presence and movements of animals using infrared light and communicated the information to a connected PC. Software (Imetronic, Pessac, France) analyzed rat movements within each compartment of the apparatus, measured the number of entries and the time rats spent in each compartment. 2.4.2. Procedure Four weeks after surgery, which corresponds to the stabilization of the DA denervation (Paillé et al., 2007; Maia et al., 2012), the animals were recruited to the CPP test. The experiments consisted of 4 phases: habituation, pretest, a conditioning period, and a test phase. 2.4.2.1. Habituation. Rats were handled for 5 days and during the last two days they received an injection of a vehicle solution (drug-free solution). 2.4.2.2. Pretest. The next day, the animals were placed in the central alley. During the pretest, that took place under drug-free conditions, animals received only vehicle and were free to explore the entire apparatus for 15 min. The time spent in each compartment during this 15 min session was measured. 2.4.2.3. Conditioning period. It consisted of one session of 30 min per day during 8 days. The animals were confined to one compartment by blocking entrance to the tunnel. Each animal had one session with a drug injection alternated the second day with an injection of a vehicle solution. The animals were divided into two groups according to a counterbalanced design. During a single session one animal group received the drug tested, in the compartment where they spent less time in pretest, while the other received only the vehicle solution, in the compartment where they spent the most time in pretest. This procedure was alternated on the other day to avoid the influence of circadian variability. During place conditioning, the rats received four drug-paired sessions and four vehicle paired sessions. 2.4.2.4. Test. The next day, the guillotine doors were removed and the animals were introduced into the apparatus by placing them in the central alley and did not receive any drug or vehicle. The time spent in each compartment during a 15 min session was measured. Data were presented as the mean time for each animal group (sham and 6OHDA) spent in the drug-paired compartment during the pretest phase and during the testing day. A significant increase of the time spent in the drug-paired compartment associated with a decrease of the time spent in the two other

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compartments during the test phase in comparison with times assessed during the pretest phase was considered as a CPP. The reverse was considered as a CPA. 2.5. Motor performance Animals of the control groups e receiving only the vehicle solution during CPP test, i.e. 8 sham and 13 lesioned animals, were used to determine their basal motor performance during the 6-week study, without interfering with treatment (Fig. 1). In addition, we also measured body weight (g) to monitor the general condition of the animals. 2.5.1. Rotarod The rotarod test was performed before surgery and at 2, 4 and 6 weeks after surgery. Locomotor impairment was determined on an accelerating rotarod treadmill (TSE systems GmbH, Bad Homburg, Germany). Before testing, rats were habituated to the instrument at a constant (4 rpm, 5 min) and accelerated speed (40 rpm, 5 min, 5 times) for three consecutive half days. A testing session was performed on the fourth consecutive day. The rotarod was accelerated progressively from 4 rpm to 40 rpm over 5 min. The time that rats remained balanced on the device was scored. The rotarod test results for each animal represent the average time (s) spent on the rod for the last 3 sequences on the testing session (mean  SD). 2.5.2. Locomotor activity Software from the CPP apparatus gave information on the number of entries on each compartment, the movement made at the back, front, and back and forth in each compartment. Locomotor activity performance represents the sum of movements performed in each compartment for each animal (mean  SD) in 15 min. The input number is the sum of entries in the compartments made for each animal (mean  SD) in 15 min. Data were obtained at week 4 and 6. In addition, we measured the locomotor activity in 6-OHDA-lesioned animals on the test vs. the pretest day of the CPP test for L-dopa and for the three DRAs at different doses tested to characterize the effect of DA treatment.

2.7. Data analysis and statistics The body weight and the motor performance were compared by a two-way ANOVA (group and time) for repeated measures (time), followed by a post-hoc StudenteNewmaneKeuls test if ANOVA was significant (p < 0.05). For the CPP data, differences between pretest and test values for the drug-paired compartment were analyzed by Student’s t-test for dependent samples. Significance was considered p < 0.05 level. Next, results of CPP for each tested drug were compared by a two-way ANOVA (group and drug doses), followed by a post-hoc Studente NewmaneKeuls test if ANOVA was significant (p < 0.05). The total number of TH immunoreactive cells were compared by a one-way ANOVA (group), followed by a post-hoc StudenteNewmaneKeuls test if ANOVA was significant (p < 0.05). Analyses were made with Statistica software (StatSoft France, Maisons-Alfort).

3. Results We initially focused on characterizing the 6-OHDA lesion impact on the motor behavior of the lesioned-rat and DA neuron cell survival in the SNc and VTA. To this end, motor behaviors were investigated using the rotarod and locomotor activity analysis in animal controls, i.e. animals receiving no DA therapy, in order to characterize the evolution of the bilateral denervation model for 6 weeks. In addition, we also measured the body weight of animals. TH-positive cell counts were performed using IHC. Moreover, we measured the locomotor activity in all animal groups (all treatment groups, 6-OHDA-lesioned/sham animals) in order to characterize the effect of DA treatment and thus evaluate whether there are relationships between locomotor improvement and development of a motivation to take this treatment.

2.6. Tyrosine hydroxylase (TH) immunostaining At the end of the CPP procedure, 19 shams and 66% of 6-OHDA-lesioned animals (thus 77 6-OHDA-lesioned rats) used in the CPP test were randomly selected for TH immunostaining. Animals were deeply anesthetized by an i.p. injection of sodiumpentobarbital solution (60 mg/kg), and perfused through the heart with a 4% paraformaldehyde solution. Brains were removed and post-fixed in the same fixative for an additional hour at 4  C. The brains were alcohol-dehydrated, xylene cleared and automate-included (Microm Microtech, Francheville, France) in a paraffin resin. Brains were coronal-sectioned (7 mm) using a microtome (Microm Microtech, Francheville, France). Three coronal sections were cut at the level of the anterior, medial and posterior part of the SNc (at interaural coordinates A, 4.44 mm; A, 3.70 mm and A, 2.96 mm respectively, based on the stereotaxic atlas of Paxinos and Watson, 1986). The medial section overlapped also the VTA. The sections were mounted on SuperFrost plus glass slides and stored at 20  C until specific treatment. Sections were deparaffinized, hydrated through an alcohol gradient and three washes of phosphate buffer solution (PBS). Endogenous peroxydase was removed by incubating the sections in a 3% H202 solution. DA neurons were revealed immunohistochemically (IHC) using a TH primary antibody (diluted at 1:500; Chemicon international). Sections were incubated overnight at 4  C in the primary antibody. They were then washed several times in PBS and incubated in a biotinylated secondary antibody (Dako, France) solution for 30 min at room temperature. Sections were washed and the reaction was amplified by incubating the sections in a streptavidin horse-raddish peroxydase solution (Dako, France) for 30 min. The reaction was revealed using diamino-benzidine as a chromogen. The sections were then dehydrated, cleared and mounted for microscopic observations. Photomicrographs of immunostained sections were captured and all image analysis was completed using ImageJ software (ImageJ v1.41, National Institute of Health, USA). In the two hemispheres and for the three sections through the SNc and for the section of VTA, the number of TH positive cells were counted using ImageJ software. For each animal group, data were the total number of cells in the three sections of the SNc and in the section of the VTA and were expressed as the percentage of the number of cell bodies measured for the shams (mean  SD).

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3.1. General behavior of animals After surgery rats that received the 6-OHDA were weak and not capable of feeding themselves. They were fed (formula, first stage, Guigoz, France) two to three times per day, 8e10 days post-surgery (Fig. 1, nursing). Despite nursing, 20% of the 6-OHDA-lesioned rats died at two weeks after surgery. None of the sham lesioned rats died during the study. Then 6-OHDA-lesioned animals became able to move progressively and to drink and feed normally. They recovered progressively from the surgery and had almost normal locomotor activity from the fourth week after surgery and then stayed stable over time. Focusing on the body weight of control animals, we showed that control 6-OHDA-lesioned animals (n ¼ 13) were significantly leaner than sham control (n ¼ 8) (ANOVA: F ¼ 28.96, degrees of freedom (df) ¼ 19, p < 0.001) in the first week after surgery (Fig. 2, week 1: 6-OHDA-lesioned, 211  24 g vs. sham, 251  19 g, ***p < 0.001) and until the end of this protocol experiment (week 2: 6-OHDAlesioned, 240  22 g vs. sham, 310  26 g, ***p < 0.001; week 3: 6OHDA-lesioned, 273  29 g vs. sham, 352  32 g, ***p < 0.001; week 4: 6-OHDA-lesioned, 310  29 g vs. sham, 377  29 g, ***p < 0.001; week 5: 6-OHDA-lesioned, 342  22 g vs. sham, 397  32 g, ***p < 0.001; week 6: 6-OHDA-lesioned, 330  34 g vs. sham, 413  35 g, ***p < 0.001). Moreover, we observed that following the use of the D1 receptors agonist specifically for the two higher doses, motor behavior was defined as hyperactive (rapid movement in the cages,

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CPP Test Sacrifice

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Fig. 1. Experiment protocol. 4 weeks after surgery, the animals were recruited to the CPP test and were sacrificed in order to validate the dopaminergic denervation. Their locomotor activity was also monitored during the study.

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3.2.2. Locomotor activity There was no significant difference in the sum of movements between 6-OHDA-lesioned and sham animals at both the fourth and the sixth weeks (Fig. 4A). However, a slight but significant difference was observed in the input number to the CPP apparatus between 6-OHDA-lesioned and sham animals at both the fourth (ANOVA: F ¼ 31.98, df ¼ 19; p < 0.05; Fig. 4B, 6-OHDA-lesioned: 17  8 vs. sham: 25  3, #p < 0.05) and sixth weeks (6-OHDAlesioned: 16  8 vs. sham: 25  5, #p < 0.05). There was also no difference in the sum of movements and in the input number of the apparatus for the sham and 6-OHDAlesioned animals between the pretest and the day of the Test of CPP for L-dopa and the three DRAs, whatever dose tested (data not shown). Fig. 2. Evolution of the body weight. After surgery, 6-OHDA-lesioned animals (n ¼ 13) had a body weight (g) significantly lower than sham animals (n ¼ 8) throughout the experimental protocol (***p < 0.001).

jumps, escaping their cage...), both in 6-OHDA-lesioned and sham animals (observations made after administration of treatment, therefore not objectively measured). 3.2. Motor performance 3.2.1. Rotarod Locomotor impairment of animals controls was investigated using the rotarod technique and revealed significant differences in lesioned animals (n ¼ 13) starting from the second week when compared to the preoperative stage (Fig. 3, ANOVA: F ¼ 24.82, df ¼ 19, p < 0.001; week 2: 55  40 s vs. preoperative stage: 169  25 s, ***p < 0.001; week 4: 76  36 s vs. preoperative stage: 169  25 s, ***p < 0.001; week 6: 95  29 s vs. preoperative stage: 169  25 s, ***p < 0.001). Their activity seemed to improve over time but remained different from their preoperative score. There was a lesion impact and indeed a significant decrease was observed between the 6-OHDA-lesioned and sham (n ¼ 8) animals, at the different stages studied, starting from the second week (week 2: 6-OHDA-lesioned, 55  40 s vs. sham, 178  46 s, ###p < 0.001; week 4: 6-OHDA-lesioned, 76  36 s vs. sham, 155  42 s, ###p < 0.001; week 6: 6-OHDA-lesioned, 95  29 s vs. sham, 159  15 s, ###p < 0.001). The performance of the sham animals was stable during the study.

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Fig. 3. Locomotor impairment. The motor performance (s) as tested by the rotarod at 2, 4 and 6 weeks post-surgery. A significant motor performance difference was observed between 6-OHDA-lesioned (n ¼ 13) and preoperative animals at all stages studied (***p < 0.001). Moreover, there was a significant decrease between 6-OHDAlesioned and sham animals at all stages tested (###p < 0.001). There was no difference in sham animals (n ¼ 8).

3.3. TH immunostaining To analyze the impact of 6-OHDA lesions (Fig. 5A), TH immunostaining was processed in both the SNc and VTA of lesionedanimals (N ¼ 77) and compared to the sham animals (N ¼ 19). TH labeling (Fig. 5B) revealed a significant difference in the number of TH positive neurons between the two animal groups in VTA (ANOVA: F ¼ 158.40, df ¼ 94; p < 0.001; 6-OHDA-lesioned: 72  15 vs. sham: 145  33, ***p < 0.001) and SNc (ANOVA: F ¼ 713.85, df ¼ 94; p < 0.001; 6-OHDA-lesioned: 50  16 vs. sham: 187  22, ***p < 0.001). There was a 47% and 71% DA cell loss in VTA and SNc respectively. 3.4. Drug-induced CPP The role of DRAs and L-dopa effects on drug reward was evaluated in 6-OHDA-lesioned and sham animals using the CPP paradigm. 3.4.1. Cocaine-induced CPP Cocaine, at the dose of 10 mg/kg, i.p., induced a significant increase of the time spent in the drug-paired compartment between the pretest phase and the test phase in both 6-OHDAlesioned (n ¼ 10, pretest: 193  58 s vs. test: 472  106 s, ***p < 0.001) and sham (n ¼ 8, pretest: 209  74 s vs. test: 435  88 s, ***p < 0.001) animals. This increase was associated with a significant decrease of the time spent in the two other compartments (neutral and saline-paired compartment). Thus, cocaine at the dose of 10 mg/kg induced a CPP in both sham and 6-OHDAlesioned rats. There was, however, no significant difference between 6-OHDA-lesioned and sham animals (Fig. 6). 3.4.2. L-dopa did not induce CPP L-dopa at each dose used did not induce CPP in sham (n ¼ 8/ dose) and 6-OHDA-lesioned (n ¼ 8/dose) animals. There was also no difference between L-dopa-injected and control animals (Fig. 7). 3.4.3. D1 receptors agonist-effect on CPP There was a different dose effect of the D1 receptors agonist induced CPP in 6-OHDA-lesioned and sham animals (Fig. 8, n ¼ 8/ dose). At the three tested doses, SKF81297 induced a significant increase of the time spent in the drug-paired compartment in sham rats (1 mg/kg: pretest: 266  34 s vs. test: 403  30 s, ***p < 0.001; 3 mg/kg: pretest: 213  26 s vs. test: 396  87 s, ***p < 0.001; 9 mg/ kg: pretest: 257  47 s vs. test: 326  63 s, *p < 0.05). This increase was associated with a decrease of the time spent in the neutral and the saline-paired compartments. Thus, at the three tested doses, SKF81297 induced a CPP in sham rats. Furthermore, at higher doses (3 and 9 mg/kg), SKF81297 induced a significant decrease of the time spent in the drug-paired compartment in 6-OHDA-lesioned

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Fig. 4. Locomotor activity. (A): Sum of movements. The average movement within the CPP apparatus was measured in 6-OHDA-lesioned (n ¼ 13) and sham (n ¼ 8) rats at 4 and 6 weeks post-surgery. There was no significant difference between the 2 groups (6-OHDA-lesioned vs. sham). (B): Input number. The total number of entry from each compartment of the CPP apparatus was measured in 6-OHDA-lesioned (n ¼ 13) and sham (n ¼ 8) rat at 4 and 6 weeks post-surgery. A significant decrease between 6-OHDA-lesioned and sham animals at all stages tested (#p < 0.05) was observed.

rats (3 mg/kg: pretest: 301  39 s vs. test: 210  89 s, *p < 0.05; 9 mg/kg: pretest: 307  39 s vs. test: 166  41 s, ***p < 0.001). This decrease was associated with an increase of the times spent in the two other compartments and reflected a CPA. Moreover, a significant difference between the two groups of animals was observed for the time spent in the drug-paired compartment at 3 mg/kg (ANOVA: F ¼ 31.98, df ¼ 14; p < 0.001; 6OHDA-lesioned: 210  89 s vs. sham: 396  87 s, ###p < 0.001) and 9 mg/kg (6-OHDA-lesioned: 166  41 s vs. sham: 326  63 s, ##p < 0.01). 3.4.4. D2 receptors agonist-induced CPP At low doses (0.1 mg/kg), the bromocriptine had no significant effect on both 6-OHDA-lesioned (Fig. 9, n ¼ 8/dose) and sham (n ¼ 8/dose) animals. At 1 mg/kg, the bromocriptine induced a significant increase of the time spent in the drug-paired compartment in both 6-OHDA-lesioned (pretest: 209  16 s vs. test: 412  88 s, ***p < 0.001) and sham (pretest: 228  21 s vs. test: 438  68 s, ***p < 0.001) animals. This increase was associated with a decrease of the times spent in the two other compartments and reflected a CPP. Conversely at 10 mg/kg, the bromocriptine induced a significant CPA in 6-OHDA-lesioned animals (pretest: 290  41 s vs. test:

(A)

205  42 s spent in the drug-paired side, **p < 0.01; the decrease in the time spent in the drug-paired compartment was associated with increased times spent in the two other compartments), whereas the same dose induced a CPP in sham animals (pretest: 214  31 s vs. test: 328  66 s spent in the drug-paired compartment, ***p < 0.001; associated with decreased times spent in the two other compartments). A significant difference was observed at 10 mg/kg in sham compared to 6-OHDA-lesioned animals for the time spent in the drug-paired compartment (ANOVA: F ¼ 64.29, df ¼ 14; p < 0.001; 6-OHDA-lesioned: 205  42 s vs. sham: 328  68 s, ###p < 0.001). 3.4.5. D3 receptors agonist-induced CPP PD128907 did not induce an effect in both 6-OHDA-lesioned (Fig. 10, n ¼ 9) and sham (n ¼ 8) animals at low doses (0.3 mg/kg). However, 1 mg/kg induced a significant increase of times spent in the drug-paired compartment in both 6-OHDA-lesioned (n ¼ 9, pretest: 213  47 s vs. test: 462  14 s, ***p < 0.001) and sham (n ¼ 8, pretest: 201  49 s vs. test: 414  92 s, ***p < 0.001) animals. This increase was associated with a decrease of the times spent in the neutral and the saline-paired compartments and reflected a CPP. At 3 mg/kg, PD128907 had no significant effect in both 6OHDA-lesioned (n ¼ 8) and sham (n ¼ 8) animals.

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Fig. 5. TH immunostaining. A: Effect of 6-OHDA lesions on TH expression in the SNc and VTA. TH immunohistochemistry of a sham rat (a) and a 6-OHDA treated rat (b). SNc ¼ substantia nigra compacta, VTA ¼ ventral tegmental area; scale bar ¼ 200 mm. B: TH-immunoreactive cells. The total number of TH positive neurons was measured in 6OHDA-lesioned (n ¼ 77) and sham (n ¼ 19) animals and expressed as percentage of values obtained for sham rats. Significant differences in both the VTA and SNc were observed between 6-OHDA-lesioned and sham animals (***p < 0.001).

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To explore the DA motivation in PD, we used a rat model in which SNc was partially destroyed by a bilateral 6-OHDA injection that induces DA depletion (Paillé et al., 2007). This model represents the most likely motor dysfunction features of PD. The high death rate of the animals obtained after bilateral DA denervation constituted a limiting factor for the success of this model (Schwarting and Huston, 1996). This was counterbalanced by intense nursing/caring for the animals, which increased survival and limited post-surgery death to 20% in our case. By focusing on the body weight of our animals as an indicator of general condition, we show that control 6-OHDA-lesioned animals were significantly leaner than the sham control animals in the first week after surgery and until the end of this experiment protocol (week 6). A recent study showed that weight loss was less marked with a unilateral 6OHDA lesion in the MFB (Morris et al., 2010).

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4.1. Model-characterization/motor performance

We further improved this model by using desipramine in order to selectively target DA neurons only (Pioli et al., 2008). A DA denervation was obtained in the SNc (71%) and the VTA (47%). This result is consistent with the DA denervation described in PD patients (e.g. more than 60% in the SNc and around 43% in the VTA) (German et al., 1989). A significant difference in rotarod performance that assessed coordination was observed in control depleted animals. Furthermore, denervated animals made fewer entries into the apparatus compartments. This should be considered as an index of exploration rather than motor activity, and illustrates a decrease in motivation. Pioli et al. reported that rats with bilateral partial lesions of the VTA (25%) during free exploration of the Y maze lost their innate behavior and their alternation performance remained around chance level (Pioli et al., 2008). However, compared to

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This is a pioneer study exploring the DRAs and L-dopa rewarding effect in a bilateral partial 6-OHDA-lesioned rat using the CPP paradigm. The hedonistic/rewarding effects of these drugs were compared to cocaine for which the motivational properties are well established.

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4. Discussion

Fig. 8. Dose effect of SKF81297, the D1 receptors agonist, on CPP test. A significant CPA was observed in 6-OHDA-lesioned animals (n ¼ 8/dose) at 3 mg/kg (*p < 0.05) and 9 mg/kg (***p < 0.001) of SKF81297, when pre-conditioning values were compared to post-conditioning values, while it had no effect at 1 mg/kg. Conversely, in the sham group, SKF81297 at the three tested doses (n ¼ 8/dose) caused a CPP (*p < 0.05; ***p < 0.01 statistically significant difference pre- vs. post-conditioning values). A significant difference was also observed between 6-OHDA-lesioned and sham animals at 3 mg/kg and 9 mg/kg (###p < 0.001).

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Fig. 6. Effect of cocaine on CPP test. Cocaine (10 mg/kg) induced a CPP in sham (n ¼ 8) and 6-OHDA-lesioned (n ¼ 10) animals. (***p < 0.001, statistically significant difference pre- vs. post-conditioning values (paired t-test)).

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Fig. 9. Dose effect of bromocriptine, the D2 receptors agonist, on CPP test. A significant CPP was observed in 6-OHDA-lesioned animals (n ¼ 8/dose) at 1 mg/kg (***p < 0.001) and CPA at 10 mg/kg (**p < 0.01) when pre-conditioning values were compared to post-conditioning values, while it had no effect at 0.1 mg/kg. In the sham animals (n ¼ 8/dose), the bromocriptine at 1 mg/kg and 10 mg/kg caused a CPP (***p < 0.001, statistically significant difference pre- vs. post-conditioning values). A significant difference was also observed between 6-OHDA-lesioned and sham animals at 10 mg/kg (###p < 0.001).

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Fig. 10. Dose effect of PD128907, the D3 receptors agonist, on CPP test. A significant CPP was observed in 6-OHDA-lesioned (0.3 mg/kg, n ¼ 9; 1 mg/kg, n ¼ 9; 3 mg/kg, n ¼ 8) and sham (n ¼ 8/dose) animals at 1 mg/kg (***p < 0.001, statistically significant difference pre- vs. post-conditioning values). No significant difference was observed between 6-OHDA-lesioned and sham animals at all doses.

shams, the 6-OHDA-lesioned animals had almost normal locomotor activity four weeks after surgery, suggesting that the mobility capacity of the animals was not disturbed. Moreover, whatever the treatment and the dose administered in both animal models, there was no significant difference in their locomotor activity on the test day vs. the pretest of the CPP test (data not shown). This can be explained by the fact that on the day of the test, the animals had no treatment for at least 24 h. Thus, the change in animal behavior assessed by CPP on the test day could only be explained by the rewarding or aversive effect of the tested drugs. Despite the limitation of the model concerning coordination and motivation, we show that cocaine is able to induce a CPP both in DA denervated and sham animals and thus validate this model for testing the motivational properties of DRAs. 4.2. Reward/aversive properties of drugs tested with CPP paradigm 4.2.1. Specificity In this study, we chose bromocriptine as the D2 receptors agonist even if there are controversies on the specificity of the drug. Some authors have claimed that bromocriptine is also a D2 and D3 receptor agonists (De Keyser et al., 1995; Perachon et al., 1999), while for others it is more D2R than D3R (Sautel et al., 1995; Emilien et al., 1999; Millan et al., 2000; Seeman et al., 2005). Sumanirole, known to be highly specific for D2R (De Paulis, 2003; McCall et al., 2005) was not chosen because no effective dose was available in the rat for the CPP test, while this data was available with bromocriptine (Hoffman et al., 1988). SKF81297 and PD128907 are respectively clearly highly selective for D1R (Emilien et al., 1999; Neumeyer et al., 2003) and D3R (Newman-Tancredi et al., 1995; Sokoloff and Schwartz, 1995). In addition, they have already been used in CPP tests in naive animals (Khroyan et al., 1997; Abrahams et al., 1998; Gyertyán and Gál, 2003; Graham et al., 2007). 4.2.2. Sham animal model Concerning CPP assessment, the three DRAs tested show biphasic (inverted U-shaped) curves with significant dose effect for the intermediate dose. These results are in line with previous reports showing similar results in naïve animals (Hoffman et al., 1988; Khroyan et al., 1997; Graham et al., 2007), although others reported a CPA with a D3 receptors agonist at the same dose (Gyertyán and Gál, 2003). Differences could be explained by methodological issues such as housing conditions, strain and CPP protocol (Tzschentke, 1998, 2007).

This result shows that DA denervation is not a condition for appreciating the hedonistic values of DRAs. Actually, in humans, Steiner and Wirguin reported in 2003 that they have listed five non-parkinsonian patients who were under treatment with L-dopa for an incorrect diagnosis of PD or for restless legs syndrome (Steiner and Wirguin, 2003). Attempts to wean the patients off these medications resulted in psychological and physiological symptoms and signs of withdrawal. In addition, Holman described compulsive gambling and shopping among patients taking DRAs for treatment of fibromyalgia (Holman, 2009). These results confirm that DRAs have a rewarding effect in naïve animals and in humans, close to psychostimulants drugs such as cocaine and support the assumption that DRT possess reinforcing properties and could lead to potential abuse. 4.2.3. 6-OHDA-lesioned animal model D1 receptors agonist caused significant CPA at intermediate and high doses, while there was no effect at the low dose. From these results, it can be concluded that this agonist mainly promotes aversion in denervated animals compared to control. D1R is the most widespread DARs and is expressed at a higher level in the brain than any other DAR (Dearry et al., 1990). D1R mRNA and protein have been found in the striatum, the NAc, and the olfactory tubercle. In addition, D1R has been detected in the limbic system, hypothalamus, and thalamus. A sensitization process was observed at the level of D1R in the dorsal striatum in 6OHDA-lesioned animals. In contrast to D2R (Creese et al., 1977; Lee et al., 1978), D1R hypersensitivity is not explained by a change in the number of DARs nor by a change in its subcellular localization (Savasta et al., 1988; Hervé et al., 1993; Muriel et al., 2002) but by increase in their coupling to adenylate cyclase. Rates of Gaolf are increased in the rat striatum denervated with 6-OHDA, and in the striatum of PD patients (Hervé et al., 1993; Corvol et al., 2004). The CPA observed in denervated animals could be explained by a hypersensitivity of D1R in the limbic systems and more specifically in the NAc, with a leftward shift in the doseeeffect curve of D1 receptors agonist as observed in the CPP test. Other studies are needed to test this hypothesis. However, D2 receptors agonist showed a differential effect. This agonist induced a CPP at the intermediate dose, while it had aversive properties at high doses in the denervated rats only, like the D1 receptors agonist. Like D1R, D2R mRNA is present in all dopaminoceptive regions of the rat brain especially in limbic regions, the cerebral cortex and striatum (Weiner et al., 1991). The sensitization of D2R has also been described in the dorsal striatum in denervated animals and included an up-regulation of DARs expression (Creese et al., 1977; Rinne et al., 1990; Brooks et al., 1992; Kaasinen et al., 2000) at the early stage of PD. In postmortem brain studies of untreated PD patients, elevated D2R density was also found, whereas DRT was associated with normal levels of D2R binding (Lee et al., 1978; Guttman and Seeman, 1985). Animal studies have shown that a reduction as well as no change of striatal D2R binding after chronic L-dopa or DRAs exposure has been reported in rats with a unilateral lesion of the SNc (Reches et al., 1984; Jenner et al., 1998). However our results cannot be explained solely by an upregulation of D2R since its agonist also had a rewarding effect on sham animals. The functional D2R hypersensitivity could be mediated by an increase in the activity of downstream effectors that mediate D2R signaling, as suggested for D1R. In DA-denervated animals, D3 receptors agonist produces a CPP similar to that obtained for the sham animals only for 1 mg/kg but does not induce CPA for the higher dose in PD animals. In addition, our results suggest that the D3 receptors agonist at 1 mg/kg does not cause any difference compared to cocaine, whereas a significant

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difference is observed between D2 receptors agonist and cocaine. Thus, even if the comparison is indirect, the motivational properties of D3 receptors agonist seem higher than the D2 receptors agonist for the same dose. For D3R it would seem that there is an undeniable implication in the compulsive use of drugs (Lévesque et al., 1995; Guillin et al., 2004; Le Foll et al., 2005). D3R is predominantly expressed in the NAc, but also in the VTA and in the amygdala, which are brain structures implicated in drug dependence (Diaz et al., 2000; Le Foll et al., 2005). The fact that D3R leads to CPP in both animal models could be explained by the specific localization of D3R in parts of the limbic system. The lack of effect of the higher dose may be due to the lack of specificity of PD128907 (Pugsley et al., 1995) with strong stimulation of D2R, which can induce CPA and counterbalance the activation of D3R. It is interesting to note that D1R and D3R are colocalized on striatal neurons, where they form heteromers and produce synergistic effects in reserpinized mice (Marcellino et al., 2008), suggesting that a role of this receptor is to obtain a stronger DA response. In addition, D1-dependent sensitizations of D3R binding sites and mRNA have been observed in the Caudate-Putamen of dyskinetic parkinsonian rats (Bordet et al., 1997). Interestingly, in these rats, sensitization of D3R also occurs in limbic areas, such as the NAc (Bordet et al., 1997). Moreover, in the 6-OHDA-lesioned rat and 1-methyl- 4-phenyl1,2,3,6-tetrahydropyridine treated non-human primate models of PD, as well as in humans affected by PD, D3R expression is decreased in the shell of the NAc (Lévesque et al., 1995; Bordet et al., 1997; Morissette et al., 1998; Ryoo et al., 1998). In the 6-OHDA lesioned rat, the repeated intermittent administration of L-dopa induces motor behavioral sensitization associated with a progressive increase of D3R mRNA in denervated dorsal striatum and the NAc core (Bordet et al., 1997). Therefore, D3R supersensitivity may be involved in both extrapyramidal motor control and reward processes (Fenu et al., 2009). The fact that L-dopa does not induce any effect could be explained by the non specificity on DARs. Thus, CPP linked to the stimulation of D2R/D3R could be also counterbalanced by the stimulation of D1R. However, it would be interesting to test the combination of these treatments, L-dopa and DRAs, which could potentiate the CPP performance of L-dopa, in the induction of such behaviors. Finally, this study shows that cocaine induces a similar CPP both in sham animals and in a PD model suggesting for DA-denervated animals, other neurotransmitters are probably implicated in the appearance of the cocaine rewarding effect (Kuhar et al., 1991; Sora et al., 2001; Hnasko et al., 2007). In conclusion, this study confirms the predominant roles of D2R and most specifically D3R in rewarding properties of DRT. Under our experimental conditions, we failed to demonstrate a greater motivational effect of DRAs and particularly for the D3 receptors agonist in DA-denervated animals compared to sham rats. Other studies are needed to explore the role of chronic exposure to DRAs, as DDS is diagnosed in PD patients after chronic DRT, in the genesis and the severity of these behaviors in animal models of PD. Disclosure/conflicts of interest Each author has no conflict of interest concerning this study. Acknowledgments We thank Christelle Baunez and Philippe Damier team for helping us to develop this study in our laboratory.

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