Invited reviewSerotonin-dependent depression in Parkinson’s disease: A role for the subthalamic nucleus?
Highlights
► Depression is the most common neuropsychiatric co-morbidity in Parkinson’s disease. ► Low 5-HT and altered basal ganglia activity may be critical to develop depression. ► STN DBS has shown to inhibit 5-HT neurotransmission in animal models. ► Inhibited 5-HT transmission may underlie STN DBS depressive-like side effects.
Introduction
Parkinson’s disease (PD) is a common neurodegenerative disorder, with a rising incidence from 0.3 to 4.4 per 1000 person-years in the age category over 50 years (de Lau et al., 2004). Although PD is well characterized by motor symptoms including akinesia, tremor, rigidity and postural instability, it is often accompanied by non-motor symptoms such as depression, anxiety and dementia. Depression is observed in as many as 35–40% of PD patients (Cummings, 1992, Reijnders et al., 2008) and significantly contributes to the disease burden. A dysfunctional serotonin (5-hydroxytryptamine; 5-HT) system is generally regarded as a risk factor for depression. Several lines of evidence suggest a decrease of 5-HT neurotransmission in PD, most likely caused by pathological changes of the 5-HT neurons in the midbrain raphe nuclei.
The 5-HT innervation of the forebrain principally arises from two large clusters of 5-HT neurons located in the dorsal (DRN) and median raphe nucleus (MRN).
This ascending 5-HT system innervates each of the basal ganglia nuclei, which collectively malfunction due to loss of dopamine in the nigrostriatal pathway to generate the motor symptoms of PD (Di Matteo et al., 2008, Lavoie and Parent, 1990, Steinbusch, 1981). The basal ganglia are not only involved in motor regulation but also in associative and limbic functions (Temel et al., 2005a). This relationship is evident at neuroanatomical and functional levels, and has been observed clinically by recent studies involving deep brain stimulation (DBS) of the subthalamic nucleus (STN). Thus, it is established that high-frequency electrical stimulation of electrodes bilaterally implanted into the STN restores motor deficits in advanced PD, but often produces unwanted behavioural effects, including depression (Appleby et al., 2007, Takeshita et al., 2005, Temel et al., 2006b). The well-established links between depression and 5-HT raise the question of whether altered basal ganglia activity and changes in the 5-HT system might interact to generate risk of depression in PD patients.
This review evaluates the role of 5-HT in PD-related depression and includes a review of recent findings in the field of STN DBS. First, changes in 5-HT neurotransmission and 5-HT related markers in PD are reviewed. This is followed by an overview of the evidence of degenerative processes in the midbrain raphe nuclei in PD. Consideration of interactions between the basal ganglia and 5-HT system then precedes a final section, which discusses interactions between the STN and the 5-HT system.
Section snippets
Depression and PD
As noted above, clinical depression is the most common neuropsychiatric disorder in PD (Cummings, 1992, Reijnders et al., 2008). The presence of depression has a negative impact on the quality of life of PD patients and their families (Schrag et al., 2000, Schrag et al., 2004). Several studies have shown that there is an increased incidence (circa 2-fold) of depression before the onset of PD (Leentjens et al., 2003, Shiba et al., 2000). In this context, depressive symptoms can be present as
5-HT markers in PD
Much evidence suggests that a dysfunctional 5-HT neurotransmission is an important risk factor for depression. For example, decreased 5-hydroxyindoleacetic acid (5-HIAA) levels, a 5-HT metabolite, are found in the cerebrospinal fluid of patients suffering from depression, and anti-depressant effects are achieved with elevation of synaptic 5-HT availability using SSRIs. Earlier studies already showed that levels of 5-HIAA in the cerebrospinal fluid of PD patients were significantly decreased in
5-HT challenge tests in PD
Findings from studies of 5-HT markers in cerebrospinal fluid and post-mortem brain tissue provide clear evidence of a 5-HT dysfunction in PD patients. Pharmacological 5-HT challenges have also been used to explore the state of the 5-HT system in PD. An impaired neuroendocrine response to 5-HT drug challenges such as the 5-HT releasing agent fenfluramine, is commonly found in depressed patients (Cleare et al., 1996, Cleare et al., 1998, Cowen, 2008, O’Keane and Dinan, 1991). Fenfluramine
Changes in 5-HT transporter binding in PD
The integrity of the 5-HT system can also be evaluated by measuring 5-HT transporter (5-HTT) availability using positron emission tomography (PET) and single photon emission computed tomography (SPECT) scans with various radioactive ligands (Table 1). A loss of 5-HTT binding is thought to reflect a decrease of 5-HT terminals and even a loss of 5-HT neurons (Meyer, 2007). In depressed patients there are reports of increased 5-HTT binding which has been interpreted as causing decreased 5-HT
PD-related pathology of the midbrain raphe nuclei
The evidence of a decrease in 5-HT markers and 5-HTT radioligand binding in PD points to a possible pathological loss in 5-HT neurons. Although the classical hallmark of PD pathology is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), the degenerative process is far more extensive and also affects non-dopaminergic systems. Braak et al. proposed that degeneration in PD starts in the medulla oblongata with Lewy bodies and neurites in the dorsal motor nuclei of
Non-5-HT mechanisms of depression in PD
Although a dysfunctional 5-HT system is generally regarded as an important risk factor for depression, other theories emphasise the role of catecholamine neurotransmitters. In addition to changes in dopamine, several earlier post-mortem PD studies reported Lewy bodies and neuronal degeneration in the noradrenergic locus coeruleus (Forno et al., 1986, Halliday et al., 1990b, Paulus and Jellinger, 1991). Also significant decreases in levels of both dopamine and noradrenaline have been found in
The basal ganglia and 5-HT
The evidence of dysfunctional 5-HT neurotransmission in PD symptoms raises the question of its role in the motor symptoms. The classical model of the basal ganglia motor circuit offers an explanation of the consequences to motor function resulting from degeneration of the dopaminergic nigrostriatal pathway, although even this explanation is incomplete. For example, whilst this model explains bradykinesia, it falls short in explaining the generation of tremor. A PET study reported that the
The 5-HT innervation of the subthalamic nucleus
Immunohistochemistry studies show a fine network of 5-HT fibres with sporadic varicosities in the STN of rats, cats and monkeys (Lavoie and Parent, 1990, Mori et al., 1985, Parent et al., 2010, Steinbusch, 1981) that originates from the DRN (Canteras et al., 1990). This 5-HT network in the STN is most dense and more unevenly distributed in the monkey in comparison to the rat (Lavoie and Parent, 1990, Mori et al., 1985, Parent et al., 2010) (Fig 1). One group found that in the monkey the 5-HT
The influence of 5-HT in the subthalamic nucleus
The most abundant 5-HT receptors expressed in the STN are the 5-HT1A, 5-HT1B, 5-HT2C and 5-HT4 subtypes (Bruinvels et al., 1993, Eberle-Wang et al., 1997, Pompeiano et al., 1994, Stanford et al., 2005, Wright et al., 1995, Xiang et al., 2005). Application of 5-HT to STN slices has been found to evoke multiple responses with an increase in spontaneous STN neuronal firing being mediated via 5-HT2C and 5-HT4 receptors (Shen et al., 2007, Stanford et al., 2005, Xiang et al., 2005) and a decrease
The influence of the subthalamic nucleus on the 5-HT system
The role of the STN in cognitive and limbic functions is emphasized by behavioural changes induced by subthalamotomy and/or the application of STN DBS in patients with advanced PD. Bilateral subthalamotomy was shown to improve cognition and mood over a follow-up period of two years (Alvarez et al., 2005). However, bilateral lesions of the subthalamic nucleus in the 6-OHDA rat model of PD alleviated motor deficits but induced impulsivity with increased premature responding in a reaction time
Synopsis
The frequent occurrence of depression in PD is a prevalent but complex problem. Although often missed or underestimated, depression can seriously influence the course of PD and the quality of life of patients. The presence of a dysfunctional 5-HT system in PD is evident from reported changes in 5-HT biochemical markers, structural changes in the DRN and MRN, and abnormal 5-HT neuronal activity patterns. However, this may not be sufficient to cause vulnerability to depression in PD. Similarly,
Acknowledgements
This study has been funded by the Netherlands Organisation for Scientific Research (Mosaic grant for ST and Veni grant for YT), the Dutch brain foundation (HS 2008(1)-32 and 2009(2)-26 to YT) and Parkinson’s UK (TS).
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