High frequency stimulation of the subthalamic nucleus has bene®cialantiparkinsonianeffectsonmotorfunctionsinrats, butlessef®ciencyinachoicereactiontimetask YassineDarbaky, 1 Claude Forni, 2 Marianne Amalric 1 and Christelle Baunez 1 1 Laboratoire de Neurobiologie de la Cognition, Centre National de la Recherche Scienti®que, 31 Chemin Joseph Aiguier, 13402 Marseille cedex 20, France 2 Laboratoire de Neurobiologie Cellulaire et Fonctionnelle, Centre National de la Recherche Scienti®que, 31 Chemin Joseph Aiguier, 13402 Marseille cedex 20, France Keywords: basal ganglia, circling behaviour, cognitive functions, deep brain stimulation, dopamine, substantia nigra Abstract Chronic subthalamic nucleus high frequency stimulation (STN HFS) improves motor function in Parkinson'sdisease. However, its ef®cacyoncognitivefunctionandthemechanismsinvolvedarelessknown.TheaimofthisstudywastoassesstheeffectsofSTNHFS in hemiparkinsonian awake rats performing different speci®c motor tests and a cognitive operant task. Unilateral STN HFS applied in unilaterallyDA-depletedratsdecreasedtheapomorphine-inducedcirclingbehaviourandreducedcatalepsyinducedbytheneuroleptic haloperidol. DA-depleted rats exhibited severe de®cits in the operant task, among which the inability to perform the task was not alleviated by STN HFS. However, in a few animals showing less impairment, STN HFS signi®cantly reduced the contralateral neglect induced by the lesion. These results are the ®rst to demonstrate a bene®cial effect of STN HFS applied in awake rats on basic motor functions. However, STN HFS appears to be less effective on impaired cognitive functions. Introduction Striataldopaminedepletion,thehallmarkofParkinson'sdisease(PD), is associated with an abnormal activity of the subthalamic nucleus (STN)(Robledo&Fe Âger,1991).InactivationoftheSTNhasthusbeen proposed as an alternative therapy to dopaminergic treatments in Parkinsonism (Bergman et al., 1990). STN lesions alleviate motor de®citsobservedinmonkeyandrodentmodelsofPD(Bergman etal., 1990; Aziz et al., 1991; Baunez et al., 1995; Henderson et al., 1999; Phillips & Brown, 1999) while, in patients, accidental infarct of the STN or surgical lesions signi®cantly reduce parkinsonian symptoms (Sellal etal.,1992;Gill&Heywood,1997).InPD,therapeuticlesions oftheSTN,ahighlyvascularizedandsmallstructure,may,however, produce hemiballism and morbidity. Neurosurgeons have therefore developed high frequency stimulation (HFS) technique which was foundtogreatlyalleviateparkinsonianmotorsymptomswhenapplied totheSTN(Limousin etal.,1995).Bene®cialeffectsarealsoobserved onmuscularrigidityandrestingtremorin1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine(MPTP)±treatedmonkeys(Benazzouz etal.,1993; Gao et al., 1999). The effects of STN HFS on cognitive functions remain, however, poorly documented (Benabid et al., 2001; Woods et al., 2002), although recent experiments in rats pointed out the involvementofSTNinattentionalandmotivationalfunctions(Baunez & Robbins, 1997, 1999; Baunez et al., 2002). In anaesthetized rats, STN HFS is followed by a decrease in neuronal activity in the STN target structures [e.g. substantia nigra pars reticulata (SNr) and entopeduncular nucleus] (Benazzouz et al., 1995, 2000) and, in 6-hydroxydopamine (6-OHDA)-lesioned rats, STN HFS normalizes the increased expression of the metabolic marker in these structures (Salin et al., 2002). STN HFS is therefore thought to inactivate the STN by reducing the overactive out¯ow in basal ganglia outputs. However, contradictory results by Windels et al. (2000) have shown that STN HFS increases the extracellular level of glutamate in the substantianigra parsreticulata (SNr)inanaesthetizedrats,whileSTN lesions decrease it (F. Windels, N. Bruet, A. Poupard, C. Baunez, A. Bertrand,I.Lena&M.Savasta,unpublishedobservations).Allthese recent data have been obtained in rats with stimulation parameters which were not proven to have bene®cial effects on awake animals. Therefore, the aim of the present study was to investigate the behaviouralconsequencesofSTNHFSinaratmodelofparkinsonism. WeexaminedtheeffectsofSTNHFSinratswithunilateral6-OHDA nigrostriatal lesions on classical sensorimotor tests assessed by mea- sures of circling behaviour induced by apomorphine and on haloper- idol-inducedcatalepsy.WealsotestedtheeffectsofSTNHFSonmore complex integrative processes involved in the execution of a later- alized choice reaction time (CRT) task, particularly appropriate for unilateral 6-OHDA models, including planning of action, response selection and initiation. Materials and methods Animals Male Long-Evans rats (Janvier, France; n  63) were housed in pairs andmaintainedona12-hlight±darkcycle.Theywerekeptat85%of their free feeding weight by food restriction. Water was provided ad European Journal of Neuroscience, Vol. 18, pp. 951±956, 2003 ß Federation of European Neuroscience Societies doi:10.1046/j.1460-9568.2003.02803.x Correspondence: Dr Christelle Baunez, as above. E-mail: baunez@lncf.cnrs-mrs.fr Received 7 January 2003, revised 15 May 2003, accepted 29 May 2003