Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia Bai-Yun Zeng a , Mahmoud M. Iravani a , Michael J. Jackson a , Sarah Rose a , André Parent b , Peter Jenner a, ⁎ a NDRG, School of Biomedical and Health Sciences, King's College, London, UK b Centre de Recherche Université Laval Robert-Giffard 2601, Chemin de la Canardière, Local F-6500 Beauport, Quebec, Canada G1J 2G3 abstract article info Article history: Received 11 June 2010 Revised 13 July 2010 Accepted 1 August 2010 Available online 14 August 2010 Keywords: Serotonin Tryptophan hydroxylase Primate L-DOPA Dyskinesia Hyperinnervation of the striatum by serotoninergic (5-HT) terminals occurs after destruction of the dopaminergic nigro-striatal pathway. Recent studies have suggested that non-physiological release of dopamine (DA) formed from levodopa in these serotoninergic terminals underlies abnormal involuntary movement (AIMs) induction in 6-OHDA lesioned rats. In the present study, we used tryptophan hydroxylase (TPH) immunohistochemistry to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and the induction of dyskinesia by levodopa alter the morphology of 5-HT fibres in the striatum of common marmosets. The caudate–putamen of normal monkeys contained numerous fine and smooth TPH positive fibres and numerous varicose fibres, but a marked hyperinnervation of TPH positive fibres characterised by a significant increase in the number and diameter of TPH positive axon varicosities was noted in the dorsal caudate and putamen of MPTP-intoxicated monkeys but not the globus pallidus. In MPTP-intoxicated marmosets that had received chronic levodopa treatment to induce dyskinesia, a further increase in the number and enlargement of TPH positive axonal varicosities in both caudate nucleus and putamen was evident. Following LID induction, a similar pattern of increase was also observed in the external segment of the globus pallidus, but only a significant varicosity enlargement was seen in the internal pallidal segment. These results confirm that striatal 5-HT hyperinnervation follows nigro-striatal pathway loss and provide the first evidence in primates that chronic levodopa treatment and the onset of dyskinesia are associated with a marked hypertrophy of striatal 5-HT axonal varicosities. These findings support the concept that altered 5-HT function may contribute to the genesis or expression of LID. © 2010 Elsevier Inc. All rights reserved. Introduction Levodopa therapy in Parkinson's disease (PD) reverses motor deficits but prolonged treatment and disease progression leads to the development of motor complication, including dyskinesia (Nutt, 1990; Chase et al., 1998; Fahn, 2000; Zesiewicz et al., 2007; Jenner, 2008). The pathogenic mechanisms leading to the induction of dyskinesia remain unclear but there is an almost absolute requirement for nigral dopaminergic neuronal loss (Schneider 1989; Boyce et al., 1990; Nutt, 1990). Consequently dyskinesia do not develop in normal individuals and those with restless leg syndrome treated with levodopa for many years (Cotzias et al., 1967; Mones et al., 1971; Rajput et al., 1997; Conti et al., 2007). In addition, normal monkeys do not develop dyskinesia in response to pharmacological doses of levodopa (Paulson 1973; Sassin, 1975; Schneider 1989; Boyce et al., 1990). Conversely, non-human primates and humans with a high degree of nigral denervation induced by exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydro- chloride (MPTP), rapidly develop motor complications on levodopa administration (Schneider, 1989; Nutt, 1990). The loss of dopaminergic input to the striatum is thought to lead the development of the permanently ‘abnormal’ basal ganglia that then responds aberrantly to drug treatment (Obeso et al., 2000). Levodopa induces far more dyskinesia than dopamine agonists and this has been attributed to its short duration of action producing a non-physiological pulsatile stimulation of post-synaptic dopamine receptors and underpins the concept of continuous dopaminergic stimulation as a means of avoiding dyskinesia induction (Jenner, 2004; Olanow et al., 2006). However, there has been recent interest in the involvement of serotoninergic (5-hydroxytryptamine, 5-HT) neurones in the genesis and expression of levodopa induced dyskinesia in PD. Pharmacological studies have shown 5-HT1a and 5-HT1b agonists inhibit dyskinesia in 6-hydroxydopamine (6-OHDA) lesioned rats with abnormal involuntary movements (AIMs) induced by levodopa exposure (Muñoz et al., 2009). Similar findings have been obtained in levodopa primed MPTP treated primates exhibiting dyskinesia (Iravani et al., 2003, 2006; Taylor et al., Neurobiology of Disease 40 (2010) 599–607 Abbreviations: PD, Parkinson's disease; 5-HT, 5-hydroxytryptamine; TPH, trypto- phan hydroxylase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochlo- ride; 6-OHDA, 6-hydroxydopamine. ⁎ Corresponding author. Neurodegenerative Disease Research Centre, School of Health and Biomedical Sciences, King's College, London SE1 1UL, UK. Fax: +44 207 848 6034. E-mail address: peter.jenner@kcl.ac.uk (P. Jenner). Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2010.08.004 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi