PD初期ではl-dopa由来の過剰なdopamine (DA)は dopamine transporter (DAT)とD2 auto-receptorにより摂取、貯蔵され、線条体のDA終末より分泌される。L-dopaを投与すると、セロトニンニューロンに存在するAADC (Aromatic-L-Amino Acid Decarboxylase (AADC)により、DAが合成される。PDの進行期では、神経変性が進み、l-dopaの効率性を媒介するDA終末はさらに少なくなる。この時期ではBで示されるように、セロトニン求心路がl-dopa 由来のDAの貯蔵と分泌の主たる部位として登場する。セロトニンニューロンはDAT もD2 auto-receptorも有していないため、過剰に分泌されたDAをコントロールできない。そのためにジスキネジアが誘発される。
serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT1A) agonistであるタンドスピロン（セディール）がジスキネジアの抑制に有効であった。胎児脳移植を受けたPD患者の
ジスキネジアの成因として、過剰なセロトニンニューロンの神経支配がIn vivo imagingにて報告され、5-HT1A agonist (buspirone)投与にジスキネジアが減弱した（3）。
Carta, M., Carlsson, T., Kirik, D., & Björklund, A. (2007). Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain, 130(7), 1819-1833.
The brainstem serotonin neurons are known to be to a varying degree affected by the disease process (Agid and Javoy-Agid, 1987; Hornykiewicz, 1998). Nevertheless, the serotonin innervation of the striatal complex remains relatively intact in most PD patients and may thus play a role not only in the control of motor behaviour, but also in the handling of systemic administered l-DOPA (Lavoie and Parent, 1990; Nicholson and Brotchie, 2002). The serotonin neurons have been shown to be able to convert exogenous l-DOPA to DA, and store and release DA in an activity-dependent manner (Ng et al., 1970, 1971; Hollister et al., 1979; Arai et al., 1994, 1995, 1996; Tanaka et al., 1999; Maeda et al., 2005). l-DOPA-derived DA acting as a ‘false transmitter’ in serotonergic neurons may be particularly important in advanced stages of the disease when a major part of the nigrostriatal DA system has degenerated and the remaining DA neurons are in a compromised functional state (Miller and Abercrombie, 1999; Tanaka et al., 1999; Kannari et al., 2001). The integrity of the serotonin system may thus be an important factor in determining the efficacy of l-DOPA therapy in PD patients, and in particular in the development and maintenance of the most problematic side-effect of l-DOPA medication, the drug-induced dyskinesias. The ability of l-DOPA to induce dyskinesia increases over time, resulting in a gradual loss of the therapeutic window of l-DOPA medication in more advanced PD patients (Mouradian et al., 1989). In a recent PET imaging study, de la Fuente-Fernandez et al. (2004) have shown that peak-dose dyskinesias in advanced PD patients are associated with excessive swings in synaptic DA (and hence DA receptor occupancy) induced by oral l-DOPA administration. This raises the possibility that, in the absence of a functional striatal DA innervation, l-DOPA-derived DA is released in a non-physiological ‘dysregulated’ manner.
In the present study we provide evidence that DA released as a false transmitter from the residual serotonin innervation may be the source of this dysregulated DA release. The results show that l-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA) lesion rat model, resembling peak-dose dyskinesia in l-DOPA-treated PD patients, is critically dependent on the integrity and function of the serotonin innervation, while the therapeutic effect of systemically administered l-DOPA is maintained primarily by spared DA terminals.
Induction of l-DOPA-induced dyskinesia by dysregulated DA release from the serotonin terminals. In early stages of PD, represented in A, enough spared striatal DA innervation remains to mediate the therapeutic, anti-parkinsonian, effect of l-DOPA. At this stage of the disease, exogenous l-DOPA-derived DA is taken up, stored and released by striatal DA terminals. Excessive swings in extracellular DA levels are prevented by auto-regulatory feedback mediated by the DA transporter and the D2 auto-receptors present on the dopaminergic terminals. As neurodegeneration progresses, fewer and fewer DA terminals will remain to mediate l-DOPA efficacy. At this more advanced stage, represented in B, the serotonin afferents will emerge as the prime site for storage and release of l-DOPA-derived DA. Due to the lack of normal auto-regulatory feedback, however, and concomitant depletion of the endogenous serotonin transmitter by DA accumulating in the storage vesicles, DA released from serotonin terminals will be poorly regulated, resulting in uncontrolled, excessive swings in DA release. The progressive loss of regulated DA release from spared DA terminals, and the gradual emergence of the serotonin afferents as the predominant source of dysregulated DA release would be therefore responsible for dyskinesia. The 5-HT1A and 5-HT1B receptor agonists, as represented in C, are proposed to act by dampening the excessive swings in l-DOPA-derived DA release from the striatal serotonergic terminals. Note that for simplicity 5-HT1A receptors are positioned at the terminal level, but are indeed located at the level of the cell body and dendrites of serotonin neurons.
- Maeda T, Nagata K, Yoshida Y, Kannari K. Serotonergic hyperinnervation into the dopaminergic denervated striatum compensates for dopamine conversion from exogenously administered l-DOPA. Brain Res 2005; 1046: 230-3.
The aim of this study was to determine whether raphe-striatal serotonergic neurons of adult rats with extensive nigro-striatal dopaminergic denervation are induced by injection of exogenous L-DOPA to contain dopamine. Double-labeling immunofluorescence study was conducted. In the lesioned striatum of rats that received L-DOPA, serotonergic hyperinnervation was observed, and dopamine was detected in serotonergic varicose fibers. These findings suggest that striatal serotonergic hyperinnervation can compensate for the lost function of dopaminergic neurons.
- Tanaka, H., Kannari, K., Maeda, T., Tomiyama, M., Suda, T., & Matsunaga, M. (1999). Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. Neuroreport, 10(3), 631-634.
The effect of L-dihydroxyphenylalanine (L-DOPA) on extracellular dopamine (DA) in the striatum was determined by microdialysis in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with and without the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At the same time the intensity of L-DOPA-induced rotational behavior was assessed. In 6-OHDA-lesioned rats treated with 5,7-DHT, L-DOPA (50 mg/kg, i.p.) increased extracellular DA only to 20% of that measured in animals not treated with 5,7-DHT. Like-wise, 6-OHDA-lesioned rats treated with 5,7-DHT exhibited a significantly lower number of L-DOPA-induced rotations. These results suggest that serotonergic terminals in the striatum can convert exogenously administered L-DOPA into DA that can be released into the extracellular space.
- Politis, M.et al. (2010). Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Science Translational Medicine, 2(38), 38ra46-38ra46.
Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson’s disease. The mechanisms underlying these dyskinesias are not well understood, and it is not known whether they are the same as in the dyskinesias induced by l-dopa treatment. Using in vivo brain imaging, we show excessive serotonergic innervation in the grafted striatum of two patients with Parkinson’s disease, who had exhibited major motor recovery after transplantation with dopamine-rich fetal mesencephalic tissue but had later developed off-medication dyskinesias. The dyskinesias were markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT1A) agonist, which dampens transmitter release from serotonergic neurons, indicating that the dyskinesias were caused by the serotonergic hyperinnervation. Our observations suggest strategies for avoiding and treating graft-induced dyskinesias that result from cell therapies for Parkinson’s disease with fetal tissue or stem cells.
Tandospirone citrate, a selective 5-HT1A agonist, alleviates L-DOPA-induced dyskinesia in patients with Parkinson’s disease. No to Shinkei = Brain and Nerve 2002, 54(2):133-137
A rapid and excessive increase in extracellular dopamine(DA) after L-DOPA administration is considered one of the major causes for L-DOPA-induced peak-dose dyskinesia. Therefore, inhibition of excessive rise in L-DOPA-derived DA is likely to be an ideal treatment for L-DOPA-induced dyskinesia. Based on our previous experimental studies that 8-OH-DPAT, a potent 5-HT1A agonist, attenuates an increase in L-DOPA-induced extracellular DA in the striatum of the rat model of Parkinson’s disease, we hypothesized that L-DOPA-induced dyskinesia in patients with Parkinson’s disease is alleviated by a 5-HT1A agonist. In the present study, we administered tandospirone citrate, a selective 5-HT1A agonist, to patients with Parkinson’s disease suffering from L-DOPA-induced dyskinesia. Tandospirone(15-60 mg/day) was administered to 10 patients with L-DOPA-induced peak-dose dyskinesia. Twelve weeks after tandospirone treatment, duration of dyskinesia, subjective and objective severity of dyskinesia, and parkinsonian features were evaluated. Severity of dyskinesia was decreased in 5 patients; among these, 3 patients experienced slight worsening of parkinsonian features. Four patients showed no change in dyskinesia; among these, 2 patients showed worsening of parkinsonian features. One patient had slight worsening of dyskinesia without any change in parkinsonian features. The present study demonstrated that tandospirone is effective in alleviating L-DOPA-induced dyskinesia in 50% of the patients. However, at the same time 50% patients showed slight worsening of parkinsonian features. Both the anti-dyskinetic effect and the worsening of parkinsonian features are thought to be induced by tandospirone’s potent 5-HT1A agonistic activity. Diverse effect of tandospirone may be caused by its partial agonist activity on 5-HT1A receptors, or may indicate that other causes for the expression of dyskinesia exist apart from excessive rise in brain DA levels. Administration of a 5-HT1A agonist is a choice for patients with dyskinesia if the care is taken so as not to induce worsening of parkinsonian features. Further studies such as double-blind trials are needed to confirm the usefulness of a 5-HT1A agonist for L-DOPA-induced dyskinesia.