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