Lateral habenula as a link between dopaminergic and serotonergic systems contributes to depressive symptoms in Parkinson's disease

Highlights

• We examined whether LHb lesions improve depressive symptoms of PD rats by increasing 5-HT levels of RN.

• LHb showed an obviously elevated cytochrome c oxidase in PD rats with depressive-like behavior.

• LHb lesions decreased the immobility time of FST in PD rats with depressive-like behavior.

• LHb lesions increased the climbing time of FST in PD rats with depressive-like behavior.

• LHb lesions increased the 5-HT levels of raphe nuclei in PD rats with depressive-like behavior.

Abstract

Degeneration of substantia nigra dopaminergic neurons is a key pathological change of Parkinson's disease (PD), and its motor consequences have been widely recognized. Recently, mood disorders associated with PD have begun to attract a great deal of interest, however, their pathogenesis remains unclear. PD is associated with not only degenerative changes in dopaminergic neurons in the substantia nigra but also changes in serotonergic neurons in the raphe nuclei. The abnormalities in central 5-hydroxytryptamine (5-HT) neurotransmission are thought to play a key role in the pathogenesis of depression. The lateral habenula (LHb) is closely related to the substantia nigra and raphe nuclei, and its hyperactivity is closely related to the pathogenesis of depression. In this study, we screened rats with depressive-like behaviors from PD model animals and found that cytochrome c oxidase activity in the LHb of these rats was twice that seen in the control rats. In the forced swim test, LHb lesions caused a decrease in depressive-like behavior of PD rats as indexed by decreased immobility times and increased climbing times. Additionally, LHb lesions caused an enhance in 5-HT levels in the raphe nuclei. These results suggest that LHb lesions may improve depressive-like behavior in PD rats by increasing 5-HT levels in the raphe nuclei. Thus, LHb contributes to the depressive-like behavior in PD rats via mediating the effects of dopaminergic neurons in the substantia nigra on serotonergic neurons in the raphe nuclei.

Introduction

Parkinson's disease (PD) is a degenerative disease of the central nervous system that is common in the elderly population. The motor symptoms of PD are well recognized and have been the focus of much research. However, the mood disorders observed in most PD patients, such as depression (Shulman et al., 2001, McDonald et al., 2003), should not be neglected because they seriously affect the quality of life and prognosis of PD patients; furthermore, they can be a direct cause of death in these patients (Carod-Artal et al., 2007, Rahman et al., 2008).

Numerous studies have shown that movement disorders result from reductions in dopamine levels in the striatum, which are caused by degenerative pathological changes in midbrain substantia nigra pars compacta dopaminergic neurons. Therefore, the clinical application of levodopa can obviously improve movement disorders in PD patients (Zibetti et al., 2013). However, PD-related affective disorders are associated with not only disrupted dopamine systems but also nondopamine system changes, such as central 5-hydroxytryptamine (5-HT) system disorders (Scatton et al., 1983). It is widely known that a decreased 5-HT level in the raphe nuclei is related to the onset of depression (Stockmeier et al., 1998, Gray et al., 2013). Interestingly, Mayeux et al. (1984) have shown that 5-hydroxyindoleacetic acid levels in the cerebrospinal fluid of PD patients with depression were lower than those in the normal controls and nondepressed PD patients. In addition, serotonin reuptake inhibitors can markedly improve depressive-like symptoms in PD patients (Devos et al., 2008). Consequently, depression symptoms in PD patients may be the result of the interaction of the two systems. Recently, Bastide et al. (2014) have reported that immediate early gene levels, such as ΔFosB, change not only in basal ganglia structures but also in other brain areas of PD-model animals given levodopa to induce hyperactive behavior, including the lateral habenula (LHb). The structure may link the substantia nigra dopamine system with the raphe nucleus serotonin system, thus playing important roles in PD patients with depressive-like behavior (PDD).

The LHb directly projects into the substantia nigra and raphe nucleus and it is involved in a wide range of functions related to the two structures, including cognitive and emotional functions, pain sensitivity and sleep and circadian rhythm regulation (Lecourtier et al., 2004, Shelton et al., 2012, Zhao and Rusak, 2005, Aizawa et al., 2013). In recent years, increasing attention has been paid to the role of the LHb in depression (Yang et al., 2008). It has been reported that LHb activity is enhanced in animals with depressive-like behaviors as well as in depressed patients (Caldecott-Hazard et al., 1988, Morris et al., 1999). Moreover, high-frequency deep-brain stimulation of the habenula to inhibit its activity was able to alleviate depressive symptoms in patients who could not be improved by antidepressants (Sartorius et al., 2010). Additionally, in animal models, LHb lesions were shown to improve depressive-like behavior by increasing raphe 5-HT levels (Yang et al., 2008).

To date, the relationships between the LHb and substantia nigra dopaminergic neurons, especially in reward processing, have been an area of focus as these two systems inhibit each other and act in distinct ways (Matsumoto and Hikosaka, 2007). Lesions of the substantia nigra (SN) have been shown to increase LHb glucose use rates, whereas efferent signals from the medial globus pallidus to the LHb in 6-hydroxydopamine (6-OHDA)-induced PD animals were found to be increased (Wooten and Collins, 1981). Therefore, the LHb not only directly controls substantia-nigra and raphe-nuclei activities, but it also acts as a bridge for communication between the substantia nigra dopamine system and the raphe nuclei serotonin system. Accordingly, substantia nigra dopaminergic neuron losses in PD rats were hypothesized to reverse its inhibitory effect on LHb, thereby increasing LHb suppression on the raphe neurons and decreasing 5-HT levels in the raphe nuclei. In this study, the effects of LHb lesions on depressive-like behavior and the 5-HT concentration in the raphe nuclei in PD rats were observed to determine whether the hyperactivity of LHb is involved in the pathogenesis of depression associated with PD by enhancing its inhibition on raphe nuclei 5-HT neurons.