Elsevier

Neurobiology of Disease

Volume 47, Issue 3, September 2012, Pages 393-406
Neurobiology of Disease

Serotonergic and dopaminergic mechanisms in graft-induced dyskinesia in a rat model of Parkinson's disease

https://doi.org/10.1016/j.nbd.2012.03.038Get rights and content

Abstract

Dyskinesia seen in the off-state, referred as graft-induced dyskinesia (GID), has emerged as a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. Although the mechanism underlying the appearance of GID is unknown, in a recent clinical study the partial 5-HT1A agonist buspirone was found to markedly reduce GID in three grafted patients, who showed significant serotonin (5-HT) hyperinnervation in the grafted striatum in positron emission tomography scanning (Politis et al., 2010, 2011). Prompted by these findings, this study was performed to investigate the involvement of serotonin neurons in the appearance of GID in the rat 6-hydroxydopamine model.

L-DOPA-primed rats received transplants of DA neurons only, DA plus 5-HT neurons or 5-HT neurons only into the lesioned striatum. In DA cell-grafted rats, with or without 5-HT neurons, but not in 5-HT grafts, GID was observed consistently after administration of amphetamine (1.5 mg/kg, i.p.) indicating that grafted DA neurons are required to induce GID. Strikingly, a low dose of buspirone produced a complete suppression of GID. In addition, activation of 5-HT1A and 5-HT1B receptors by 8-OH-DPAT and CP 94253, known to inhibit the activity of 5-HT neurons, significantly reduced GID, whereas induction of neurotransmitter release by fenfluramine administration significantly increased GID, indicating an involvement of the 5-HT system in the modulation of GID. To investigate the involvement of the host 5-HT system in GID, the endogenous 5-HT terminals were removed by intracerebral injection of 5,7-dihydroxytryptamine, but this treatment did not affect GID expression. However, 5-HT terminal destruction suppressed the anti-GID effect of 5-HT1A and 5-HT1B agonists, demonstrating that the 5-HT1 agonist combination exerted its anti-GID effect through the activation of pre-synaptic host-derived receptors. By contrast, removal of the host 5-HT innervation or pre-treatment with a 5-HT1A antagonist did not abolish the anti-GID effect of buspirone, showing that its effect is independent from activation of either pre- or post-synaptic 5-HT1A receptors. Since buspirone is known to also act as a DA D2 receptor antagonist, the selective D2 receptor antagonist eticlopride was administered to test whether blockade of D2 receptors could account for the anti-dyskinetic effect of buspirone. In fact, eticlopride produced complete suppression of GID in grafted animals already at very low dose. Together, these results point to a critical role of both 5-HT1 and D2 receptors in the modulation of GID, and suggest that 5-HT neurons exert a modulatory role in the development of this side effect of neuronal transplantation.

Highlights

► Modulation of 5-HT neuron release significantly affects GID in rats. ► Buspirone administration suppresses GID in rats, as seen in patients. ► D2 receptor blockade appears to contribute to the anti-GID effect of buspirone.

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by an excessive loss of dopamine (DA) neurons in substantia nigra (SN). l-3,4-dihydroxyphenylalanine (L-DOPA), as a precursor of DA, is widely used to increase central production of DA, and provide alleviation of motor symptoms. Although L-DOPA is very effective during the first years of administration, its long-term use can often cause unwanted motor side effects, in particular L-DOPA-induced dyskinesia (LID). Moreover, the efficacy of L-DOPA declines over-time, as the DA neurodegeneration progresses. Therefore, other approaches have been tested to alleviate parkinsonian symptoms, such as neural transplantation of DA precursor cells. Embryonic ventral mesencephalic (VM) cells have been transplanted into rodent (Bjorklund, 1992, Herman and Abrous, 1994, Winkler et al., 2000) and monkey (Redmond et al., 2008) models of PD, and in PD patients (Freed et al., 1992, Lindvall et al., 1992, Lindvall et al., 1994, Olanow et al., 2003, Piccini et al., 1999). While grafted cells are efficient in providing restoration of motor functions in pre-clinical PD models, the clinical results have been more variable (Lindvall and Bjorklund, 2004, Olanow et al., 2009, Winkler et al., 2005). One complication that has contributed to prevent further application of the transplantation approach in PD is the appearance of off-drug uncontrolled movements, so-called graft-induced dyskinesia (GID) in a subset of grafted patients (Freed et al., 2001, Hagell et al., 2002, Olanow et al., 2003). Although this form of uncontrolled movements persists even after withdrawal of L-DOPA medication, GID appears to share some cellular mechanisms with LID. Thus, priming with L-DOPA is required for development of GID (Lane et al., 2009b) and animals with severe pre-operative LID carry an increased risk for the development of GID (Garcia et al., 2011b). An increasing body of evidence points to the serotonin (5-HT) system as a key player in the appearance of LID in animal models (Carta et al., 2007, Carta et al., 2010, Munoz et al., 2008) and patients (Bara-Jimenez et al., 2005, Olanow et al., 2004, Rylander et al., 2010). In fact, recent animal work (Carta et al., 2007, Lindgren et al., 2010, Munoz et al., 2008) has suggested that abnormal release of DA from 5-HT neurons may be responsible for the excessive swings in synaptic DA levels observed in dyskinetic PD patients after L-DOPA administration (de la Fuente-Fernandez et al., 2004). Moreover, a significant 5-HT hyperinnervation has recently been found in caudate putamen of dyskinetic PD patients (Rylander et al., 2010).

Interestingly, a marked serotonergic hyperinnervation has also been observed in grafted patients using positron emission tomography (PET) scanning (Politis et al., 2010, Politis et al., 2011). In addition, an elevated 5-HT/DA transporter ratio has been recently measured in the striatum of a grafted patient compared to healthy normal individuals and advanced PD patients (Politis et al., 2011). The embryonic tissue used for transplantation is, in fact, known to contain a variable number of 5-HT cells, depending on the landmarks used for dissection of the fetal tissue (Carlsson et al., 2007), and Mendez et al. (2008) have reported large numbers of 5-HT neurons in VM grafts in long-term PD patients studied post-mortem. Based on these observations, it has been proposed that 5-HT neurons may play a role in the induction of GID. In support of this idea, Politis et al., 2010, Politis et al., 2011 have reported that GID is almost completely suppressed after administration of the partial 5-HT1A receptor agonist buspirone, raising the possibility that 5-HT1 receptor activation can suppress GID through inhibition of 5-HT neuron activity, as already seen for LID.

This study was designed to investigate the relative involvement of dopaminergic and serotonergic mechanisms in the development of GID. Although some form of stereotyped abnormal movements (tapping stereotypy and litter retrieval/chewing) has been reported to appear in rats after grafting in absence of any drug challenge (Soderstrom et al., 2008), abnormal movements phenotypically similar to LID can only be seen after administration of amphetamine (Carlsson et al., 2006, Lane et al., 2006), which is known to evoke massive DA release from grafted DA neurons (Zetterstrom et al., 1986). These abnormal movements can be scored with the same scale as for LID (Carlsson et al., 2006, Lane et al., 2006) and are now widely used as a convenient and reproducible model of GID (Carlsson et al., 2007, Garcia et al., 2011b, Lane et al., 2008, Lane et al., 2009a, Lane et al., 2009b). In the present study, we have used this model to investigate the involvement of 5-HT neurons in the appearance of GID, and the mechanisms underlying the anti-GID effect of 5-HT1 receptor agonists.

Section snippets

Animals

A total of 120 adult female Sprague–Dawley rats (225–250 g at purchase, Charles River, Sweden) were used in the present study and housed on a 12 h light/dark cycle (light on 7:00–19:00) with free access to food and water. All animal works were performed in accordance with regulations set by the Ethical Committee for the use of laboratory animals at Lund University.

Drugs

All the drugs were diluted in 0.9% sterile saline and injected s.c. unless otherwise stated.

Results

The study was designed to investigate the involvement of the serotonergic system in the appearance of GID in the 6-OHDA rat model of PD. 6-OHDA-lesioned rats were primed with daily injections of L-DOPA (6 mg/kg, plus benserazide), before being split into 4 groups to receive different types of transplants, as follows: DA narrow (n = 10), DA wide (n = 10), 5-HT (n = 11) and Sham (n = 8). The Drug-Naïve group (n = 5) did not receive any drug administration other than amphetamine for rotation tests.

Discussion

The involvement of the 5-HT system in GID has been considered since the discovery of its role in LID (Carta et al., 2007), and is supported by the finding of a large numbers of 5-HT neurons in the transplanted tissue of grafted PD patients (Mendez et al., 2008). The recent findings of Politis et al., 2010, Politis et al., 2011), showing a marked 5-HT hyperinnervation in the striatum of grafted patients, and a substantial reduction of GID by the partial 5-HT1A agonist buspirone, is in line with

Acknowledgments

We are grateful to Anneli Josefsson, Ulla Jarl and Bengt Mattsson for excellent technical assistance. The study was supported by grants from the Swedish Research Council, the Michael J. Fox Foundation, and by a grant of the European Commission within the 7th Framework Program (TRANSEURO).

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