Amphetamine-induced abnormal movements occur independently of both transplant- and host-derived serotonin innervation following neural grafting in a rat model of Parkinson's disease Emma Louise Lane a,b, ⁎, Patrik Brundin a, 1 , M. Angela Cenci b, 1 a Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund, Sweden b Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund, Sweden abstract article info Article history: Received 14 November 2008 Revised 23 February 2009 Accepted 24 March 2009 Available online 8 April 2009 Keywords: 6-OHDA 5,7-DHT Transplantation Graft-induced dyskinesia Ventral mesencephalon Serotonin has been postulated to play a role in the transplant-induced involuntary movements that occur following intrastriatal grafts of ventral mesencephalic tissue in the treatment of Parkinson's disease. Serotonin innervation of the striatum may be derived from either the donor graft tissue or the normal host projections from the midbrain. In two sets of experiments we study the impact of graft- versus host-derived serotonin innervation. All experiments were performed in L-DOPA treated rats with unilateral 6- hydroxydopamine lesions. As expected, following intrastriatal transplantation of embryonic ventral mesencephalon all the transplanted rats exhibited pronounced contralateral rotation in response to amphetamine and some animals also showed severe abnormal involuntary movements (AIMs). In the first set of experiments, all types of AIMs (axial, limb, orolingual and locomotor) were markedly reduced when amphetamine was co-administered with either the D 2 dopamine receptor antagonist raclopride or the D 1 receptor antagonist SCH23390. Cotreatment with the 5-HT 1A agonist 8-OH-DPAT significantly attenuated the amphetamine-induced axial and limb dyskinesias, whilst locomotor scores remained unchanged. These data point to a major role for dopamine receptors, and to a modulatory role for 5-HT 1A receptors, in post-grafting dyskinesias. In the second experiment, grafted rats exhibiting amphetamine-induced dyskinesia were subjected to 5,7-dihydroxytryptamine injections into the midbrain in order to destroy the host serotonin innervation. This intervention had no effect on either amphetamine-induced AIMs or contralateral rotation. Histological examination of all grafted rats showed similar numbers of dopaminergic neurons and a very low number of serotonin neurons within the transplants, regardless of AIMs expression. Our results suggest that amphetamine-induced AIMs in grafted animals primarily depend on an activation of dopamine receptors, and that serotonin neurons within either the grafts or the host brain play a negligible role. © 2009 Elsevier Inc. All rights reserved. Introduction Intrastriatal transplantation of embryonic ventral mesencephalic (VM) dopaminergic neurons can improve the motor symptoms of Parkinson's disease (PD) and reduce the need for pharmacological treatments (Brundin et al., 2000; Defer et al., 1996; Hauser et al., 1999). However, during follow-up evaluations of the patients, three clinical trial teams independently reported an unanticipated motor side effect in a subset of patients; exacerbation or development of abnormal involuntary movements in when ‘OFF’ anti-parkinsonian treatment (e.g. L-DOPA) during the post-transplantation period (Freed et al., 2001; Hagell et al., 2002; Olanow et al., 2003). Since then, no new clinical trials have been initiated, a state which has jeopardized not only the future of foetal tissue transplantation but also hindered the development of therapies based on other sources of dopaminergic cells (Hagell and Cenci, 2005; Winkler et al., 2005). In order to establish the cause of these abnormal movements, known as ‘graft- induced dyskinesia (GID)’, different hypotheses have been proposed. Initially it was postulated that excessive dopamine release from grafts that had grown dramatically could be responsible (Freed et al., 2001). 18 F-DOPA PET scans, demonstrated that this was not the case, but instead implicated hyperinnervated ‘hotspots’ within the host striatum (Ma et al., 2002) to be the cause of GID in the Denver/ Columbia trial. In contrast, patients in the Lund studies who displayed GID exhibited no evidence of excessive dopamine production in the graft-innervated striatum or focused hotspots of dopamine innerva- tion (Hagell et al., 2002; Piccini et al., 2005). This discrepancy also highlights potentially critical differences in the phenomenology of the different patient cohorts that presented with GID. The relationship of GID to the administration of L-DOPA also differs significantly with the Neurobiology of Disease 35 (2009) 42–51 ⁎ Corresponding author. Brain Repair Centre, Department of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3 UK. Fax: +00 44 292087. E-mail address: LaneEL@cardiff.ac.uk (E.L. Lane). 1 Shared senior authorship. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2009.03.014 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi