0022-3565/06/3192-914–923$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 319, No. 2 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 109207/3149389 JPET 319:914–923, 2006 Printed in U.S.A.

The Dopamine Agonist Piribedil with L-DOPA Improves Attentional Dysfunction: Relevance for Parkinson’s Disease

Nathalie Turle-Lorenzo, Be´atrice Maurin, Carole Puma, Claire Chezaubernard, Philippe Morain, Christelle Baunez, Andre´ Nieoullon, and Marianne Amalric Laboratoire de Neurobiologie de la Cognition Unite´ Mixte de Recherche 6155, Centre National de la Recherche Scientifique- Universite´ de Provence, Marseille, France (N.T.-L., B.M., C.P., C.B., M.A.); Institut de Biologie du De´veloppement de Marseille- Luminy, Unite´ Mixte de Recherche 6216, Centre National de la Recherche Scientifique-Universite´ delaMe´ diterrane´e, Marseille, France (A.N.); and Institut de Recherches Internationales Servier, Courbevoie, France (C.C., P.M.) Received June 8, 2006; accepted August 17, 2006 Downloaded from

ABSTRACT Cognitive deficits are often associated with motor symptoms in tive, a dose of 0.3 mg/kg administered for 3 weeks significantly Parkinson’s disease. This study investigates the ability of reverses the akinetic deficits produced by the striatal dopamine piribedil ([(methylenedioxy-3,4 benzyl)-4 pyperazinyl-1]-2 py- depletion and progressively improves attentional deficits. When jpet.aspetjournals.org rimidine), a D2/D3 dopamine (DA) receptor agonist with antag- coadministered with the dopamine prodrug L-3,4-dihydroxy- ␣ onist activity at 2A-adrenoceptors, to restore motor and atten- phenylalanine (L-DOPA) (3 mg/kg), piribedil (0.3 mg/kg) pro- tional deficits in nigrostriatal 6-hydroxydopamine-lesioned rats. motes a rapid and full recovery of preoperative performance. Subjects were trained to depress a lever, detect a stimulus These results suggest that administration of L-DOPA in combi- occurring after variable foreperiods, and release the lever nation with piribedil in a chronic treatment as either initial or quickly afterward. Striatal DA depletions produce deficits in the supplemental therapy for Parkinson’s disease might improve timing of foreperiods and prolong reaction times. Although a cognitive functions while reducing the risk for motor complica-

subchronic treatment with piribedil (0.1–2 mg/kg) is not effec- tions. at ASPET Journals on May 1, 2019

Since the discovery that patients with Parkinson’s disease revealed comparable affinities for the dopamine D3- and D2-

(PD) suffer from a dopamine deficiency in the basal ganglia, like receptors and very low affinity for the D1-like receptors the dopamine precursor L-3,4-dihydroxyphenylalanine (L- (Millan et al., 2002). The anti-akinetic activity of piribedil DOPA) has been successfully administered to supplement was first reported in reserpinized rats and in the 1-methyl- the depleted DA stores. The development of motor fluctua- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned pri- tions and abnormal involuntary movements (dyskinesia) is, mate (Smith et al., 1996, 2002). Its efficacy in controlling however, a common side effect of long-term treatment with motor symptoms of PD patients with an incidence of dyski- L-DOPA. DA receptor direct agonists are now commonly used nesia lower than that occurring in patients treated with as initial therapy to limit the exposure to L-DOPA and delay L-DOPA was recently shown (Montastruc et al., 1999; Tan et the onset of dyskinesia (Jenner, 1995). al., 2003). Chronic treatment with piribedil for a 6-month Among the current DA agonists acting directly on synaptic period in combination with L-DOPA is well tolerated and receptors in the striatum, piribedil ([(methylenedioxy-3,4 significantly improves motor symptoms in patients with non- benzyl)-4 pyperazinyl-1]-2 pyrimidine) is a centrally acting fluctuating PD (Ziegler et al., 2003). In addition to the classic drug, that shows selectivity for both D and D dopaminergic 2 3 motor symptoms, several cognitive deficits are observed in receptors and significant antagonistic action on ␣ -adrener- 2A nondemented patients with PD, even at the early stages of gic receptors (Millan et al., 2001). In the rat brain piribedil the disease (Dubois and Pillon, 1997). The pattern of cogni- tive impairment includes deficits of executive functions, such This research was supported by Centre National de la Recherche Scienti- fique, Universite´de Provence, Universite´delaMe´diterrane´e, and Institut de as planning and working memory (Brown and Marsden, Recherches Internationales Servier. 1990; Owen, 2004) and attentional deficits resembling those Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. produced by frontal lobe damage (Lewis et al., 2003). In the doi:10.1124/jpet.106.109207. MPTP-treated marmosets, it has been reported that, in par-

ABBREVIATIONS: PD, Parkinson’s disease; L-DOPA, L-3,4-dihydroxyphenylalanine; DA, dopamine; piribedil, [(methylenedioxy-3,4 benzyl)-4 pyperazinyl-1]-2 pyrimidine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; RT, reaction time; PLSD, pro- tected least significant difference. 914 Piribedil and Attentional Deficits in Parkinson’s Disease 915 allel to its efficacy in reducing behavioral motor deficits, 5 consecutive days, and the locomotor activity was recorded for 180 piribedil induced increased vigilance and awareness com- min. pared with L-DOPA (Smith et al., 2002). Piribedil, probably Statistical Analysis. Data analysis was carried out using a two- ␣ factor analysis of variance (ANOVA). When animals were injected through its 2A-adrenergic antagonist properties, was shown to increase acetylcholine release both in frontal cortex and in according to a Latin square design, we first analyzed the effects of the order of injections among the different groups. If no significant the hippocampus (Smith et al., 2002; Gobert et al., 2003). effect was found, differences between various doses over time were This action may be related to its facilitatory influence upon subjected to a two-factor ANOVA, with the different groups (doses of cognitive function. piribedil) as the independent factor and time as the repeated mea- Beside motor improvement, the possibility of restoring cog- sure. When the ANOVA revealed a significant effect, post hoc com- nitive functions (memory, reaction time, speed of information parisons were carried out using the Newman-Keuls test. The signif- processing, etc.) with DA agonists in PD represents a new icance level was taken to be p Ͻ 0.05. challenge. Thus, the aim of the present study was to test the Experiment 2: Reaction Time Task effects of piribedil on motor and cognitive deficits in a rat model of early PD. The nigrostriatal dopamine pathway was Animals. Male Wistar rats (Charles River), weighing 115 to 120 g damaged bilaterally by an intrastriatal infusion of the neu- at the start of the experiment, were housed in groups of two and maintained on a 12-h light/dark cycle with lights on at 7:00 AM. In rotoxin 6-hydroxydopamine (6-OHDA), which induces a pro- the reaction time task, rats were initially food-deprived for 24 h at gressive and selective loss of DA neurons. It has long been the start of training and subsequently food-restricted to 15 to 20 g of shown that DA depletion in the striatum produces profound laboratory chow per rat per day for the duration of the experiment to Downloaded from deficits in the reaction time (RT) paradigm in rats (Spirduso maintain them at 80 to 85% of the free food body weight. Water was et al., 1985; Amalric and Koob, 1987; Brown and Robbins, available ad libitum. 1991; Amalric et al., 1995; Smith et al., 2000; Courtiere et al., Apparatus and Operant Procedure. Experiments were con- 2005). We have previously found that rats trained to react ducted in standard experimental chambers (23 ϫ 22 ϫ 30 cm; Camp- quickly to a visual cue occurring after a variable interval are den Instruments, Cambridge, UK) placed in sound attenuated cubi- slower to react to the cue and sometimes impaired in the cles. The boxes were controlled, and the data were collected on line timing of the various intervals, depending on the extent of by a PC computer and laboratory interface (Paul Fray, Inc., Cam- jpet.aspetjournals.org bridge, UK). A retractable lever, located 5 cm above the grid floor and striatal DA denervation (Amalric et al., 1995). These deficits 4 cm below the cue light (2.8-W bulb), was extended immediately may be related to some extent to the akinesia, assessed by after the animals were placed in the experimental chambers. After increased RTs (Berry et al., 1999), and attentional dysfunc- completion of a successful trial, the food pellet was delivered to the tion that are commonly seen in PD patients (Gauntlett- food magazine in Ͻ1 s. The temporal resolution of the instrumental Gilbert and Brown, 1998). In the present study, we have setup was 10 ms. Animals were initially trained to lever press for a tested the efficacy of piribedil and L-DOPA alone or in con- 45-mg food pellet (P. J. Noyes Company, Inc., Lancaster, NH) on a junction to restore motor and cognitive deficits in 6-OHDA- schedule that provided one food pellet for every lever press (fixed at ASPET Journals on May 1, 2019 lesioned rats trained in the RT task. ratio-1 reinforcement schedule). A force of 0.8 N on the lever was required to operate the switch closure. After the rats successfully responded for Ͼ100 pellets, they were trained to hold down the lever until the onset of a cue-light located above the lever. To receive a food Materials and Methods pellet during this phase of training, rats had to wait for the cue-light Experiment 1: Locomotor Activity and then release the lever with no time limit. The interval between lever press and the cue-light onset was then progressively increased Animals. Male Wistar rats weighing 280 to 300 g on arrival from by steps of 50 ms for up to 1250 ms, after five consecutive correct Charles River (Lyon, France) were housed in groups of two per cage trials. At the final step, the intervals were fixed and randomized with food and water available ad libitum and maintained in temper- between four foreperiods (500, 750, 1000, and 1250 ms) to maintain ature-controlled conditions with an alternating 12 h light/dark cycle a high level of attention to the cue onset and prepare the motor (lights on at 7:00 AM). Behavioral measurements were conducted response. RT was measured in milliseconds between the presenta- during the animals’ light cycle. All procedures were in strict accor- tion of the cue-light and the release of the lever. The RT restriction dance with the French Ministe`re de l’Agriculture et de la Peˆche, was then progressively decreased from 2000 to 600 ms over 40 to 50 De´cret No. 87-848, October 19, 1987, and with the European Com- additional sessions. Each session ended after 100 trials, which ani- munities Council directive of November 24, 1986 (86/609/EEC). mals typically achieved within 10 to 15 min during the prelesion Apparatus. A bank of 16 individual wire (top, floor, and front testing period. Correct responses were those in which the rats re- door) and Plexiglas (side walls) photocell cages was used to measure leased the lever with RTs below the 600-ms time limit. Incorrect the locomotor activity. Each cage (40 ϫ 25 ϫ 23 cm) was fitted with responses were not rewarded and divided into two categories. If the two parallel horizontal infrared beams, 1 cm above the floor, located lever was released before the presentation of the cue-light, it was across the long axis of the cage (Imetronic, Pessac, France). Beam recorded as an incorrect response and termed a premature response. interruptions were accumulated over 1-min intervals and recorded in Likewise, if the lever was released with RTs above the 600-ms bins of 1 min by a one-line input to a microcomputer. The animals restriction time, it was recorded as an incorrect response and was were familiarized with the experimental cages during a 3-h session, termed a delayed response. Mean RTs averaged 300 ms at the final one day before the test session. On the day of testing, the spontane- part of the test. ous locomotor activity was monitored for 90 min before drug treat- Bilateral Striatal Dopamine Lesions. Animals were anesthe- ment. Four groups of animals (n ϭ 3 per group) received different tized by an i.m. injection of xylazine (15 mg/kg) and ketamine (100 doses of piribedil (0, 1, 3, or 10 mg/kg) in a different order of injection mg/kg) and placed in a stereotaxic instrument (David Kopf Instru- following a pseudo-random Latin-square design. Injections were per- ments, Tujunga, CA) with the incisor bar positioned Ϫ3.0 mm under formed every 3 days, and the animals were placed immediately the interaural line for surgical procedures based on coordinates of afterward in the locomotor activity cages for a total duration of 180 the stereotaxic atlas of Paxinos and Watson (Paxinos et al., 1985). min. After a washout period of 10 days, selected animals received Lesioned animals received a bilateral injection of 6-OHDA hydro- either 0.9% NaCl (n ϭ 4) or piribedil 1.0 mg/kg (n ϭ 8) once a day for chloride (Sigma-Aldrich, Lyon, France) (4 ␮g/␮l, 3 ␮l/side) in the 916 Turle-Lorenzo et al. striatum at the following coordinates: anteroposterior ϩ0.2 mm; delimitating the extent of the lesioned areas in each hemisphere. The lateral Ϯ3.5 mm, and dorsoventral Ϫ4.8 mm (from skull) according neuronal loss was measured in the lesioned areas by quantifying to the bregma. The sham control group received the vehicle alone gray levels, which were converted to optical density using external (ascorbate solution, 0.1 mg/ml) in the dorsal striatum. The infusion standards (calibrated density step tablet; Kodak). As no difference was made with a micropump over 9 min using a 10-␮l Hamilton was found in either the surface or the optical density measured on microsyringe, connected by a Tygon tubing fitting to the 30-gauge each side of the brain, the values obtained were averaged for statis- stainless steel injector needles. After surgery rats were allowed a tical analysis. The mean optical density of the lesioned areas was 7-day recovery period. then compared with the control optical density measured on the Drugs. Piribedil (Trivastal; Servier, Paris, France) was dissolved same striatal region in sham-operated animals and expressed as a in 0.9% saline and injected i.p. in a volume of 1 ml/kg. L-DOPA percentage of control values. methylester (Sigma-Aldrich) was dissolved with a DOPA decarbox- Data and Statistical Analysis. The number of correct, prema- ylase (benserazide,15 mg/kg) (Sigma-Aldrich) in a 0.9% saline solu- ture, and delayed responses were collapsed across each session by a tion and injected i.p. in a volume of 1 ml/kg. block of 6 days (e.g., weeks). The data were analyzed over time Experimental Procedures. After training lasting on average 2 (before and after 6-OHDA lesions and during drug treatments: ve- to 3 months, rats underwent the surgical procedure (6-OHDA le- hicle, piribedil, L-DOPA, or coadministration of piribedil and sions). Behavioral testing resumed on postoperative day 8 and the L-DOPA) using an overall two-way analysis of variance (ANOVA), 6-day per week testing schedule continued for 4 additional weeks. with one between-subject factor (GROUP) and one within-subject Dose response of piribedil. After the recovery period, the effects of factor (WEEK). As previously found, depending on the extent of 6-OHDA lesions were tested for six sessions (e.g., from days 9 to 14 striatal DA denervation produced by 6-OHDA infusions, the increase after surgery) and the subjects (n ϭ 20) were then divided into four of RTs and delayed responses after the cue may be associated or not subgroups. The different groups were injected with one of four doses with an increase of premature responses before the cue onset, re- Downloaded from of piribedil (0, 0.1, 0.3, or 1.0 mg/kg i.p., n ϭ 5 per dose) and tested flecting impulsivity and attentional dysfunction in the timing of the 1 h later in the RT task. This procedure allows the drug to reach its various intervals preceding the cue (Amalric et al., 1995). Chronic maximal effect in the brain. Piribedil was tested in a subchronic piribedil or L-DOPA treatment was thus separately analyzed in the treatment of six injections on postoperative days 15 to 20. After a group exhibiting delayed responding to the cue with no premature 3-day washout period, the same groups were injected with higher responding (named akinetic group) and in the group expressing both

doses of piribedil (2, 6, and 20 mg/kg) for six additional sessions from deficits (named attentional group). One-way ANOVAs followed by jpet.aspetjournals.org postoperative days 25 to 30. A sham-operated group of rats (n ϭ 5) post hoc tests (Fisher’s PLSD test) were used for multiple pairwise received vehicle injections (0.9% NaCl), and rats were tested in the comparisons within each group when appropriate. All statistical same conditions from days 9 to 30 postsurgery. analyses procedure were performed using Statview 5.0 program Chronic treatment with piribedil or L-DOPA. After a 7-day recov- (Abacus concept). RTs Ͼ100 ms (corresponding to real detection of ery period, the 6-OHDA lesion or surgery effects were tested over six the cue in contrast to coincident lever release) and Ͻ800 ms were sessions. The animals (sham n ϭ 32, 6-OHDA n ϭ 60) were then analyzed in selected sessions of the pre- and postoperative period divided into four subgroups, receiving one of the different treatments (before and after drug treatment) to further examine the individual every day for 3 weeks (from days 16 to 40 postsurgery): sham groups distribution of RTs. The distribution of RTs was plotted as a percent- at ASPET Journals on May 1, 2019 injected with 0.9% NaCl (n ϭ 12), 0.3 mg/kg piribedil (n ϭ 6), 3.0 age of the total number by 50-ms bins (frequency) ranging from 100 mg/kg L-DOPA (n ϭ 7), and a combination of 0.3 mg/kg piribedil ϩ to 800 ms and averaged for all subjects of a group. To analyze the 3.0 mg/kg L-DOPA (n ϭ 7); lesion groups injected with 0.9% NaCl delay-dependent speeding of the RT, RTs were averaged as a func- (n ϭ 22), 0.3 mg/kg piribedil (n ϭ 18), 3.0 mg/kg L-DOPA (n ϭ 7), and tion of the various foreperiods in all subjects during a pre- and a combination of 0.3 mg/kg piribedil ϩ 3.0 mg/kg L-DOPA (n ϭ 13). postoperative session before and after pharmacological treatment The dose of 0.3 mg/kg piribedil was selected on the basis of the and were submitted to a one-way ANOVA with two within-subject results obtained in the first experiment. The dose of 3.0 mg/kg factors (pre/postlesion and the four foreperiods). In addition, the L-DOPA was selected on the basis of previous studies showing that distribution of premature responses (expressed as a percentage of this dose induces no dyskinetic effects over a 3 weeks of treatment the total number of premature responses by 50- or 250-ms bin) was (Henry et al., 1999) and reduces 6-OHDA lesion-induced deficits in further analyzed with regard to the various foreperiods in represen- the same task (Turle-Lorenzo et al., 2005). The subjects received the tative pre- and postoperative sessions (before and after chronic treat- coinjection of 3.0 mg/kg L-DOPA (with 15 mg/kg benserazide) and 0.3 ment). Data were analyzed using a two-way ANOVA with two with- mg/kg piribedil and 1 h later were tested in the RT task. in-subject factors: pre/postlesion sessions and foreperiods. Histology. At the end of the experiment, animals were killed by decapitation. The brains were then removed and frozen to Ϫ80°C. Coronal 10-␮m tissue sections were cut at Ϫ20°C using a microtome Results cryostat (Leica CM3050) at the level of the striatum. Experiment 1: Locomotor Response to Piribedil The binding of [3H]mazindol to dopamine uptake sites in the striatum was measured according to the procedure described by As shown in Fig. 1, administration of piribedil transiently Javitch et al. (1985). In brief, sections were air-dried and rinsed for decreased rats’ locomotor activity within the first 30 min 5 min at 4°C in 50 mM Tris buffer with 120 mM NaCl and 5 mM KCl. with no further changes over the 180-min testing period. They were then incubated for 40 min with 15 nM [3H]mazindol After a nonsignificant effect of the order of injections of (specific activity 17 Ci/mmol; PerkinElmer Life and Analytical Sci- piribedil at different doses (P ϭ 0.4), the ANOVA testing the ences, Zaventem, Belgium) in 50 mM Tris buffer containing 300 mM effects of piribedil over time demonstrated a significant main NaCl and 5 mM KCl added with 0.3 mM desipramine to block the ϭ Ͻ effect of time (F17,51 31.02, p 0.01) and a significant noradrenalin transporter. Nonspecific binding was determined by dose ϫ time interaction (F ϭ 4.43, p Ͻ 0.01). Subse- incubating some sections in the same solution plus 30 mM benztro- 51,748 quent analysis performed during the exploratory phase of the pine. Sections were rinsed twice for 3 min in the incubation medium without mazindol and for 10 s in distilled water and were air-dried. test (e.g., the first 30 min after piribedil injection) (Fig. 1, Autoradiographs were generated by apposing the sections to a 3H- inset) showed a clear depressant short-term effect whatever sensitive screen (Raytest, Courbevoie, France) for 7 days and were the dose tested. Therefore in the following experiments, the further quantified with a beta imager (Fuji-Bas 5000). effects of piribedil on RT performance were tested 1 h after The surface of bilateral striatal 6-OHDA lesions was estimated by systemic injection. Data showed that during the period of the Piribedil and Attentional Deficits in Parkinson’s Disease 917

Fig. 1. Effect of the dopamine D2/D3 receptor agonist piribedil on spon- taneous locomotor activity. Three groups of animals received different doses of piribedil (0, 1, 3, or 10 mg/kg) in a different order of injection. All of the animals were placed in the photocell activity cages immediately Downloaded from after the injection and locomotor activity was recorded for a total duration significantly different from controls (p Ͻ 0.01; Fisher’s ,ء .of 180 min PLSD test after significant ANOVA). testing, there was no tolerance to the repeated injection of piribedil because subchronic treatment with a dose of 1.0

mg/kg for 5 consecutive days did not modify the locomotor jpet.aspetjournals.org response, which was depressed in the same proportion on the Fig. 2. Effects of piribedil administered to 6-OHDA-lesioned rats in the 5th day as on the 1st day (data not shown). reaction time task. Effects are measured on correct, premature, and delayed responses before () and after the 6-OHDA lesion (f). The effects are measured during various blocks of six sessions corresponding to: one Experiment 2: Reaction Time Performance block before surgery (pre), one block from days 9 to 14 after the lesion Subchronic Treatment with Piribedil. At completion (post), and two blocks during piribedil subchronic treatment. Low doses (0.1, 0.3, and 1 mg/kg, n ϭ 5 each) are tested from days 15 to 20 (first of the training phase, all animals reached a preoperative block) and higher doses (2, 6, and 20 mg/kg) from days 25 to 30 (second level of 65 to 70 correct responses with incorrect responses block) after lesion. The vertical axis gives the mean numbers of re- at ASPET Journals on May 1, 2019 ء Ϯ distributed among 25 to 30 premature and 5 delayed trials sponses S.E.M. per block for the three variables measured. , signifi- cant difference from preoperative performance (p Ͻ 0.05; Fisher’s PLSD per 100-trial session. There was no significant difference in test after significant ANOVA); #, significant difference from postopera- the prelesion baseline values for any parameter of motor tive performance (p Ͻ 0.05; Fisher’s PLSD test). performance among the groups. As illustrated in Fig. 2, stri- atal 6-OHDA lesions impaired RT performance as indicated addition, a tendency to increase premature responses was by a significant decrease in the number of correct responses also observed at that dose. Because piribedil at doses Ͼ2 ϭ compared with preoperative levels (main lesion effect F1,16 mg/kg produced deleterious effects on RT performance and 22.51, p Ͻ 0.01; Fisher’s PLSD test). Comparisons between lower doses were not active when tested in a subchronic groups showed no significant difference in correct, prema- 6-day treatment, the duration of treatment was then in- ture, or delayed responses before and after 6-OHDA lesions. creased for up to 3 weeks of daily injection with a low dose of Therefore, responses were pooled. The decrease in correct piribedil (0.3 mg/kg). performance was dependent upon variations of premature Chronic Treatment with Piribedil or L-DOPA. As and delayed responses as revealed by a significant overall found in a previous experiment (Amalric et al., 1995), effect of lesions on these parameters (main lesion effects 6-OHDA lesions disrupted performance by increasing both ϭ ϭ F1,16 5.6 and 18.67 for premature and delayed responses, delayed and premature responding in 63% of subjects (n respectively; all p Ͻ 0.05). Piribedil treatment significantly 38/60), whereas a selective effect on delayed responses was modified the number of correct, premature, and delayed re- observed in the remaining 37%. The effects of piribedil or ϭ sponses over time (F3,48 24.09, 5.24, and 9.6, respectively; L-DOPA were then separately analyzed in these two groups all p Ͻ 0.01) with no significant differences among subgroups (e.g., attentional versus akinetic, see Materials and treated with different doses. At low doses, 0.1 to 1 mg/kg Methods). piribedil had no significant effect on the deficits produced by Effects of Piribedil or L-DOPA as a Single Treatment. the 6-OHDA lesions, as all of the animals exhibited the same The striatal DA depletion severely impaired RT performance level of premature and delayed responses as observed during by dramatically increasing the number of premature res- the first postoperative week (Fig. 2). At the higher doses of 6 ponses (Fig. 3A). No recovery of preoperative levels was ob- and 20 mg/kg, piribedil markedly impaired RT performance served for the entire 4-week testing period (baseline versus by enhancing the 6-OHDA-induced increase in the number of postlesion, 1st, 2nd, and 3rd weeks for correct responses, p Ͻ delayed responses (p Ͻ 0.05; Fisher’s PLSD test). Piribedil at 0.05; Fisher’s PLSD test after significant ANOVA). In addi- 20 mg/kg decreased the number of correct responses to 24 tion, the number of delayed responses progressively in- trials/session as early as the 2nd day of injection. This effect creased over time and remained significantly higher than lasted throughout the 6 days of treatment (not shown). In before lesions (p Ͻ 0.05 baseline versus weeks 1 and 3). As 918 Turle-Lorenzo et al. Downloaded from jpet.aspetjournals.org

Fig. 3. Effects of chronic treatment with vehicle (n ϭ 7) (A), piribedil (0.3 mg/kg, n ϭ 9) (B), or L-DOPA (3 mg/kg, n ϭ 7) (C) in lesioned animals Fig. 4. Effects of a coadministration of piribedil (0.3 mg/kg) and L-DOPA exhibiting attentional and akinetic deficits in the RT task. The effects are (3 mg/kg) in lesioned animals (n ϭ 10) exhibiting attentional and akinetic illustrated as the mean numbers Ϯ S.E.M. of correct, premature, and deficits in the RT task. The effects are illustrated as the mean numbers Ϯ delayed responses averaged by blocks of six sessions for the pre- and S.E.M. of correct, premature, and delayed responses averaged by blocks of at ASPET Journals on May 1, 2019 significant six sessions for the pre- and postoperative periods and during the 3 weeks ,ء .postoperative periods and during the 3 weeks of treatment significant difference from preoperative performance (p Ͻ ,ء .difference from preoperative performance (p Ͻ 0.05; Fisher’s PLSD test of treatment after significant ANOVA); #, significant difference from postoperative 0.05; Fisher’s PLSD test after significant ANOVA); #, significant differ- performance (p Ͻ 0.05; Fisher’s PLSD test). ence from postoperative performance (p Ͻ 0.05; Fisher’s PLSD test). , significant difference from the 1st week of treatment (p Ͻ 0.05; Fisher’s PLSD test). shown in Fig. 3B, 0.3 mg/kg piribedil gradually reduced the number of premature responses over time with no recovery of versus 1st, 2nd, and 3rd weeks, p Ͻ 0.05). Piribedil and the preoperative level of performance, however (prelesion L-DOPA coadministration had a biphasic effect on the num- versus postlesion only, p Ͻ 0.05; Fisher’s PLSD test after ber of delayed responses, enhancing the deficit produced by significant ANOVA). In contrast, piribedil increased the 6-OHDA lesions short-term while reversing it at the last number of delayed responses at the 2nd week of treatment week of treatment (2nd week significantly different from compared with baseline (p Ͻ 0.05; Fisher’s PLSD test). A prelesion and 3rd week, p Ͻ 0.01) (Fig. 4). Piribedil or L- similar pattern of responses was observed after 3.0 mg/kg DOPA injected alone or in combination had no effect on the L-DOPA chronic treatment, although the decrease of prema- performance of sham-operated animals (Table 1). ture responses at the last week of treatment (albeit nonsig- Effects of Piribedil and L-DOPA Coadministration nificant) led to an improvement of the correct performance on Attentional Deficits. To further investigate the nature over time (3rd week versus postlesion only, p Ͻ 0.05; Fisher’s of the premature responses produced by the 6-OHDA lesion PLSD test after significant ANOVA). L-DOPA had no effect in relation to the variable foreperiods, we analyzed the dis- on the number of delayed responses at any time post- tribution of these responses (plotted by 50- or 250-ms bins) in lesion. pre- and postoperative sessions, at day 13 postlesion, in com- Effects of Piribedil and L-DOPA Coadministration. parison with the last day of piribedil and L-DOPA cotreat- As illustrated in Fig. 4, there was a significant improvement ment (Fig. 5, A and B). According to classic models of motor of RT performance in rats treated with a combination of the preparation using a simple RT procedure, when variable two drugs at same doses. The number of correct responses foreperiods are equiprobable and randomized within a series gradually returned to preoperative levels over time (post- of trials, the conditional probability of the cue onset increases lesion versus 3rd week, p Ͻ 0.01; prelesion versus 1st and as time elapses, leading to an increased level of motor prep- 2nd weeks only, p Ͻ 0.05). The increased number of prema- aration, which results in faster RTs as a function of forepe- ture responses was significantly reduced at the 1st week of riod duration (Brown and Robbins, 1991). Furthermore, the cotreatment and remained significantly lower than the distribution of the premature responses was not linear after postlesion level for the total duration of the testing period the second foreperiod (750 ms) but rather presented peaks of (post hoc test after significant one-way ANOVA, postlesion responses after the value of the cue onset (Fig. 5A). This Piribedil and Attentional Deficits in Parkinson’s Disease 919

TABLE 1 Effects of chronic treatment with vehicle, piribedil (0.3 mg/kg), L-DOPA (3.0 mg/kg) alone or in combination on correct, delayed, and premature responses in sham-operated animals The values correspond to the mean number of correct, delayed, and premature responses during different sessions: one preoperative (pre, day Ϫ2); one postoperative (post) at day 13 after the lesion, and on the last postoperative day (ϩ36) recorded immediately after vehicle, piribedil, L-DOPA, or piribedil ϩ L-DOPA injections.

Treatment Trials Pre Post Week 3 Vehicle (n ϭ 12) Correct 69 Ϯ 3.89 70 Ϯ 3.14 71 Ϯ 3.67 Premature 26 Ϯ 4.34 24 Ϯ 3.22 23 Ϯ 3.76 Delayed 5 Ϯ 1.52 6 Ϯ 1.44 6 Ϯ 1.43 Piribedil (n ϭ 6) Correct 72 Ϯ 3.89 71 Ϯ 3.85 74 Ϯ 3.99 Premature 22 Ϯ 3.58 23 Ϯ 4.31 20 Ϯ 4.72 Delayed 6 Ϯ 1.40 6 Ϯ 2.84 6 Ϯ 2.43 L-DOPA (n ϭ 7) Correct 68 Ϯ 5.56 67 Ϯ 5.68 64 Ϯ 5.45 Premature 25 Ϯ 5.34 27 Ϯ 7.74 31 Ϯ 5.24 Delayed 7 Ϯ 2.58 6 Ϯ 3.01 5 Ϯ 1.61 Piribedil ϩ L-DOPA (n ϭ 7) Correct 70 Ϯ 5.57 67 Ϯ 5.92 75 Ϯ 6.09 Premature 23 Ϯ 4.33 27 Ϯ 3.76 18 Ϯ 5.04 Delayed 5 Ϯ 1.96 4 Ϯ 0.85 6 Ϯ 1.61

p Ͻ 0.05). Interestingly, the lesions did not affect the knowl- edge of the duration of the foreperiod values since the peaks Downloaded from were preserved. As illustrated in Fig. 5B, the pattern of premature responses increasing as a function of foreperiod ϭ Ͻ length in a preoperative session (F3,36 8.64, p 0.05, significant difference in foreperiods 3 and 4 compared with foreperiods 1 and 2, p Ͻ 0.05; Fisher’s PLSD test) was dis- ϭ rupted by the lesion (F3,36 1.2, N.S.) (Fig. 4B). After chronic jpet.aspetjournals.org treatment with piribedil and L-DOPA, the pattern of preop- erative premature responses was fully recovered (significant difference in foreperiods 3 and 4 compared with foreperiods 1 and 2, p Ͻ 0.05; Fisher’s PLSD test after significant treat- ϫ ϭ Ͻ ment foreperiod interaction: F3,36 12.1, p 0.01). Effects of Piribedil and L-DOPA Coadministration on Motor Preparation. The effects of 6-OHDA lesions were at ASPET Journals on May 1, 2019 further investigated on the motor preparatory mechanisms by examining the variation of RTs with regard to the differ- ent foreperiods (Fig. 6). Preoperatively, RTs were found to be faster as the preparatory level increases (overall main effect ϭ Ͻ of foreperiod: F3,27 22.21, p 0.01). RTs were found to be significantly shorter after foreperiods 3 and 4 compared with the first foreperiod (p Ͻ 0.05; Fisher’s PSLD test, after sig- ϭ Ͻ nificant ANOVA: F3,36 4.41, p 0.01), suggesting that the animals have used the conditional probability of cue occur- rence to prepare their response. 6-OHDA lesions disrupted this pattern (nonsignificant treatment ϫ foreperiod interac- ϭ tion: F6,54 0.9) (Fig. 6). In contrast, a significant delay- dependent speeding of RTs was found after cotreatment with piribedil and L-DOPA in the last session of testing (day 36 Fig. 5. Effects on the pattern of premature responses produced by postlesion F ϭ 6.8, p Ͻ 0.01). The mean RTs in the two 6-OHDA lesions and by the coadministration of piribedil (piri) (0.3 mg/kg) 3,36 and L-DOPA (3 mg/kg). A, distribution of the premature responses (lever longest foreperiods were found to be significantly faster than release before the cue-light onset) during a preoperative (day Ϫ2: open in the shorter foreperiods (p Ͻ 0.05; Fisher’s PLSD test). area), a postoperative (day 13: solid area), and a post-treatment session Effects of Piribedil on Akinesia. As illustrated in Fig. (day 36: shaded area). The mean percentage of premature responses is plotted as a function of time in a 50-ms bin. B, Mean percentage of 7A, 6-OHDA-lesioned animals injected with vehicle exhibited premature responses is averaged for each 250-ms period preceding the a significant decrease in the number of correct responses in -significant difference from foreperiods 1 and 2 (p Ͻ 0.01; the first postoperative week compared with preoperative lev ,ء .cue onset Fisher’s PLSD test after significant ANOVA). els (mean correct 64.3 Ϯ 2.9) and remained at a level of 57 Ϯ suggests that the animals were able to use the knowledge of 3.3 correct responses throughout the 4-week testing period ϭ Ͻ the variable foreperiods to prepare their response. In addi- (F8,32 5.7, p 0.01). The decreased number of correct tion, logically the proportion of premature responses in- responses was mainly due to a significant increase in the ϭ Ͻ creased as a function of time (significant main effect of fore- number of delayed responses (F8,32 6.69, p 0.01) with no ϭ Ͻ periods: F3,27 14.71, p 0.05) (Fig. 5B). 6-OHDA lesions change in premature responding (N.S., not shown). The ef- disrupted this pattern, and the proportion of premature res- fects of the lesions were long-lasting, as no recovery was ponses was found to be similar in the different foreperiods observed for up to 40 days postlesion (preoperative versus all ϫ ϭ Ͻ (significant interaction surgery foreperiods: F3,27 3.39, postoperative weeks, p 0.05 for delayed responses; Fisher’s 920 Turle-Lorenzo et al.

amphetamine (Ecstasy)] that damage DA neurons produces variability in the level of DA depletion (Schwarting and Hus- ton, 1997). In the present study, we therefore performed quantitative analyses in selected animals, belonging to the attentional (n ϭ 10) or akinetic (n ϭ 11) group, to verify whether the size or intensity of the lesion could explain the behavioral differences. The optical density of [3H]mazindol labeling was quantitatively analyzed and compared at three different anteriority levels (1.2 mm, 0.36 mm, and Ϫ0.72 mm) within and outside the core of the lesion. The decrease of [3H]mazindol labeling in the core of the lesion averaged 87% in the attentional group and 58% in the akinetic group in comparison with sham-operated controls (Figs. 8 and 9A). A nonsignificant 15 to 22% decrease in the surrounding stri- atum was also found in both groups (Fig. 9B). A significant interaction between groups and anteriority levels was found ϭ Ͻ (F2,38 8.79, p 0.01), showing that the extension of the DA depletion was different rostrocaudally. The main difference was observed in the most rostral levels where a 41% decrease Downloaded from of labeling was found in the akinetic group compared with an 85% decrease in the attentional group (p Ͻ 0.01; simple ANOVA). At the bregma level of anteriority, on sections close to the injection site, the decrease of labeling reached 67 and 89% for the akinetic and attentional groups, respectively,

with no significant difference between the two groups. The jpet.aspetjournals.org DA depletion extended caudally to a similar extent in the two groups (65 and 86% decrease, respectively) (Fig. 9A). These results were similar to the measure of the endogenous stri-

Fig. 6. Effects of 6-OHDA lesion and piribedil ϩ L-DOPA chronic treat- atal DA contents assessed by high-performance liquid chro- ment on reaction times. Mean RTs are plotted as a function of the various matography in a previous study showing a 74% depletion of foreperiods preceding the cue-light onset. Mean RTs were measured tissue levels of DA in the posterior striatum and 53% deple- during three representative sessions: a preoperative day (day Ϫ2) and two postoperative days (days 13 and 36) corresponding to the lesion effect tion in the anterior striatum (Amalric et al., 1995). In addi- at ASPET Journals on May 1, 2019 without treatment in comparison with the end of chronic treatment, tion, a significant difference was found between the two significant difference from foreperiod 1 (p Ͻ 0.01; Fisher’s groups on the surface of the core of the lesion at these three ,ء .respectively PLSD test after significant ANOVA). different levels of anteriority. As illustrated in Fig. 9B, the surface of the lesion core in the attentional group was 1.4 PLSD test) (Fig. 7A). Piribedil at a low dose of 0.3 mg/kg mm2 rostrally and increased up to 2.2 and 1.8 mm2 caudally. normalized the number of delayed responses over time (post In contrast, the lesion in the akinetic group (Fig. 8C) was hoc test after significant one-way ANOVA: postlesion versus virtually absent rostrally (0.09 mm2) and reached a surface of 3rd week, p Ͻ 0.05, presurgery versus 1st week only, p Ͻ 0.9 and 0.8 mm2 at caudal levels (p Ͻ 0.05 at the three levels; ϭ Ͻ 0.01; Fisher’s PLSD test). As illustrated in Fig. 7B, the RT nonpaired t test after significant ANOVA: F1,19 18.8, p distribution showed a shift to the right of the curve toward 0.01). longer values after lesions and piribedil 0.3 mg/kg induced a shift back toward preoperative values. The increase in mean Discussion RTs induced by 6-OHDA lesions (prelesion versus postlesion, Ͻ p 0.05; Fisher’s PLSD test after significant ANOVA) was In the present study, we showed that the D2/D3 dopamine ␣ reduced by a 3-week treatment with piribedil (Fig. 7C). receptor agonist/ 2A-antagonist piribedil is able to counter- Histological Results. Examination of [3H]mazindol bind- act the akinetic deficits produced by partial striatal bilateral ing to DA uptake sites was undertaken to assess the extent 6-OHDA lesions in rats trained in a RT task similar to that and the localization of DA terminal loss in the striatum in used to assess motor initiation deficits in PD patients comparison with sham-operated controls (Fig. 8). Intrastri- (Gauntlett-Gilbert and Brown, 1998; Muller et al., 2000). A atal 6-OHDA infusions produced in general a lesion re- low dose of 0.3 mg/kg piribedil was effective in recovering stricted to the dorsal part of the striatum, sparing the fibers preoperative performance, provided the animals were chron- located along the lateral ventricle. There was no loss of ically injected with the drug. In conditions of extensive [3H]mazindol binding in the nucleus accumbens and the ol- 6-OHDA lesions impinging on the rostral regions of the stri- factory tubercle. Animals found to be inconsistently depleted atum, additional deficits were observed on motor readiness (e.g., asymmetric lesion or low level of depletion, n ϭ 9) were and time estimation that were reduced by piribedil at 0.3 excluded from the statistical analysis. These animals exhib- mg/kg and fully reversed with coadministration of L-DOPA at ited either no deficits or a transient increase in delayed a dose of 3.0 mg/kg. responses, which rapidly recovered within the 1st week of The positive effects of piribedil in reversing 6-OHDA le- testing. As classically reported, treatment with 6-OHDA or sion-induced akinesia and bradykinesia are in line with re- other neurotoxins [MPTP, rotenone, or methylenedioxymeth- cent studies conducted in patients with PD showing a signif- Piribedil and Attentional Deficits in Parkinson’s Disease 921

Fig. 7. Effects of chronic treatment with piribedil in animals exhibiting akinetic deficits in the reaction time task. A, the effects are illustrated as the mean numbers Ϯ S.E.M. of correct and delayed responses for the pre- and postoperative periods and during the 3 weeks of chronic treatment in 6-OHDA-lesioned animals treated with vehicle (n ϭ 9) or piribedil (0.3 mg/kg, n ϭ 9). B. Top, RT distribution is illustrated before (, pre: day Ϫ3) and after the striatal 6-OHDA lesion (f, post: day 10). Bottom, RT distribu- tion after 3 weeks of daily treatment with piribedil (u, day 42) in compari- son with preoperative distribution (). Each bar represents the RT fre- quency (percentage) by 50-ms bin from 100 to 800 ms. C, mean RTs Ϯ S.E.M. in milliseconds are illustrated Downloaded from before the 6-OHDA lesion (pre: day Ϫ3), after the lesion (post: day 10), and on day 40 postlesion correspond- ,ء .ing to the 3rd week of treatment significant difference from preopera- tive performance (p Ͻ 0.05; Fisher’s PLSD test after significant ANOVA); #, significant difference from postop- jpet.aspetjournals.org erative performance (p Ͻ 0.05; Fish- er’s PLSD test). at ASPET Journals on May 1, 2019

Fig. 8. Binding of [3H]mazindol to dopamine uptake sites at the striatal level. Photomicrographs comparing the level of [3H]mazindol labeling in striatal sections from a control subject (A) and representative subjects of Fig. 9. Quantitative analysis of the effects produced by 6-OHDA infused the attentional (B) and the akinetic (C) groups. The lack of mazindol in the striatum within (A) and around (B) the core of the lesion measured binding (dashed points) in B and C shows the different extent of 6-OHDA at three different anteriority levels related to bregma (1.2–1.08 mm, lesions in the dorsal striatum measured at different anteriority levels 0.36–0 mm and Ϫ0.72 to Ϫ0.96 mm). The effects are compared in the two (from 1.7 to Ϫ0.6 mm related to bregma). Scale bar, 1 mm. lesioned groups: akinetic (u, n ϭ 11) and attentional (f, n ϭ 10) related significant difference from control ,ء .(to the sham control group (, n ϭ 9 group (p Ͻ 0.01); ▫ significant difference between the akinetic and atten- icant improvement of motor symptoms (Montastruc et al., tional groups (p Ͻ 0.01). 1999; Ziegler et al., 2003; Simon et al., 2005). Here we found that piribedil is efficient at a low dose (0.3 mg/kg) under a activity when tested immediately after injection (Simon et chronic treatment. It is unlikely that these anti-akinetic ef- al., 2005). This is consistent with the idea that DA agonists at fects are due to a nonspecific increase of motility, because low doses preferentially activate DA autoreceptors situated doses previously found to increase locomotor activity and on the cell bodies and fibers of neurons in the nigrostriatal stereotyped behaviors in rats ranged from 50 to 100 mg/kg system. The inhibition of DA synthesis and turnover may (Dourish, 1983). In contrast, lower doses cause depression of account for the increased number of delayed responses after 922 Turle-Lorenzo et al. piribedil treatment in the attentional group and for the de- treating executive and attentional deficits, whereas some of creased exploratory behavior in the photocell cages. these are ameliorated with naphtoxazine, a compound with ␣ DA agonist drugs used to control PD vary in their profile of 1-adrenoceptor agonist-like activity (Bedard et al., 1998). ␣ action on D1/D2 and D3 receptors. Piribedil binds preferen- Selective antagonists of 2-adrenergic receptors, such as tially to D2 and D3 receptors and has no significant affinity atipamezole or idazoxan, attenuate motor symptoms (circling for the D1 receptors (Millan et al., 2001). Because the block- behavior) in unilateral 6-OHDA-lesioned rats (Chopin et al., ade of D2 receptors with selective antagonists (raclopride and 1999), whereas in MPTP-treated monkeys they facilitate the eticlopride) but not of the D1 or D3 receptor subtypes in rats action of L-DOPA (Bezard et al., 1999) and attenuate dyski- produced similar RT impairment as those observed here after nesia (Henry et al., 1999; Grondin et al., 2000). None of these 6-OHDA nigrostriatal lesions in the same task (Smith et al., studies, however, have investigated the action of these drugs 2000), it is tempting to suggest that the reversal of the on cognitive deficits in animal models of PD. We found here akinetic deficits is due to piribedil action on striatal D2 re- that repeated administration of piribedil in conjunction with ceptors. In marmoset monkeys, piribedil improves parkin- L-DOPA in rats bearing bilateral 6-OHDA lesions attenuates sonism induced by the neurotoxin MPTP (Smith et al., 1996, the attentional dysfunction and reverses the akinetic deficits. 2002), and the improvement of motor function is primarily Whether the improvement of cognitive deficits involves a ␣ attributed to activation of postsynaptic receptors in the basal selective action on 2-adrenergic receptors, ultimately mod- ganglia (Jenner, 1995). ulating cholinergic activity, or on DA D3 receptors still re- More interestingly is the finding that piribedil treatment mains to be clarified. may also affect nonmotor deficits in the same task. In addi- Clinical studies recently showed the efficacy of piribedil in Downloaded from tion to the execution of rapid movements, successful comple- the treatment of PD in monotherapy or in conjunction with tion of the RT task requires that the rats are attentive to L-DOPA (Ziegler et al., 2003). When tested in MPTP-treated the presentation of the cue-light. The loss of control over the marmosets, long-term treatment (30 days) with piribedil or “hold period” of the lever when attending to the cue-light L-DOPA produces equivalent reversal of motor deficits over after 6-OHDA lesions, illustrated by the increased number of the course of the study. In contrast to L-DOPA, however, premature responses, therefore suggests a loss of attentional piribedil produces a significantly lower degree of dyskinesia jpet.aspetjournals.org control and a disruption of motor preparation. This leads to (Smith et al., 1996, 2002). This may relate to the recent ␣ impulsive responsiveness and loss of inhibitory control, findings that blocking of 2-adrenergic receptors in PD pa- which is a general feature observed in human and nonhuman tients improves L-DOPA-induced dyskinesia without the re- primates with frontal lesions (Fuster, 1997; Evenden, 1999). appearance of parkinsonian symptoms (Colosimo and Craus, Moreover, there is a considerable overlap between the cogni- 2003). In the present study, the improvement of 6-OHDA- tive deficits observed after damage to the frontal lobes and induced deficits was not associated with abnormal dyskinetic those described in some patients with PD (Brown and Mars- movements at any time postlesion. The initial alteration of at ASPET Journals on May 1, 2019 den, 1990; Berry et al., 1999; Lewis et al., 2003; Owen, 2004). the delayed responses in the first weeks of cotreatment, Our results indicate that animals with DA denervation however, is likely to be due to a selective effect of dopamine spreading to the most rostral regions of the striatum inner- agonists injected at low dose. This was attributed to a pre- vated by the prefrontal cortex (e.g., the attentional group) synaptic action on dopaminergic terminals, therefore primar- have lost their ability to time the different foreperiods and ily reducing DA synthesis. In line with this, L-DOPA treat- are therefore unable to use the increasing probability of the ment was found to produce sedation in de novo parkinsonian cue occurrence to prepare their response to the cue. As a patients (Andreu et al., 1999; Muller et al., 2000). In the consequence, the delay-dependent speeding of RTs or “motor long-term, chronic treatment with piribedil may produce tol- readiness” seems to be disrupted by the largest DA depletion erance to these immediate effects through desensitization of in the striatum as previously found by others (Brown and DA receptors and ultimately regulate DA function on Robbins, 1991). Consistent with the idea that a dysfunction postsynaptic receptors. of the complex loop between the anterior part of the striatum The effects of piribedil on cognitive functions have not yet (e.g., caudate nucleus in human) and the prefrontal cortex been tested in parkinsonian patients, but in elderly patients. underlies the cognitive deficits of PD, excitotoxic lesions to Nagaraja and Jayashree (2001) demonstrated, after a ran- the prelimbic-infralimbic cortical areas in rats have been domized, double-blind clinical trial, that piribedil improves found to produce similar impairment of motor preparatory global cognitive function in patients with mild cognitive im- processes in the same RT task (Risterucci et al., 2003). The pairment. In young healthy volunteers, piribedil improves progressive reversal of these deficits by piribedil may be due alertness and speeds information processing (Schuck et al., ␣ to its action on D3 and/or 2-adrenergic receptors localized in 2002). Altogether, these results indicate that piribedil in the frontal cortex. Recent in vitro and in vivo investigations combination with L-DOPA may have beneficial effects on of the properties of piribedil have indeed reported a signifi- cognitive function in the early stages of PD. ␣ cant affinity for 2-adrenergic receptors in addition to the DA ␣ D2/D3 receptors (Millan et al., 2001). As an 2-adrenergic Acknowledgments receptor antagonist, piribedil was found to enhance fronto- We thank Vincent Hok for help in iconography. cortical release of acetylcholine (Newman-Tancredi et al., 2002; Gobert et al., 2003). Basal forebrain cholinergic neu- References Amalric M and Koob GF (1987) Depletion of dopamine in the caudate nucleus but not rons are well known to be involved in attentional processing, in nucleus accumbens impairs reaction-time performance in rats. J Neurosci and the loss of these neurons from the parkinsonian brain 7:2129–2134. 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