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  • br Methods br Results br Discussion br Acknowledgements br

    2024-02-06


    Methods
    Results
    Discussion
    Acknowledgements
    This work was supported by the National Institutes of Health [Grant R21 NS081429], a Pilot Grant from the Vanderbilt Conte Center supported by the National Institutes of Health [Grant P50 M096972], and by the Department of Anesthesiology at Vanderbilt University Medical Center. The sponsors had no role in study design, data collection/analysis/interpretation, or in the writing of the manuscript for publication.
    Introduction Parkinson’s disease (PD) is a neurological disorder characterized by motor disabilities, such as tremor, rigidity and bradykinesia. However, a series of non-motor symptoms including depression, anxiety, and cognitive decline can precede the classic motor defects, and have a significant impact on patients’ quality of life. Anxiety is commonly concomitant with depression, but when the depression is treated, anxiety may remain (Marsh, 2000). Therefore, anxiety is known as an increased risk factor for PD patients (Prediger et al., 2012). Several pieces of data indicate that degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SNc) underlies the motor symptoms, whereas degeneration of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) and noradrenaline (NA) neurons in the locus coeruleus (LC) associated with the non-motor symptoms (Delaville et al., 2012, Huot et al., 2011). Particularly, the 5-HT neurotransmitter system undergoes degeneration in PD, not only including loss of 5-HT neurons in the DRN, but also lower cortical 5-HT levels and alterations in various subtypes of 5-HT receptor (Huot et al., 2011). The 5-HT6 receptor is G-protein-coupled receptor, which is positively coupled to adenylyl cyclase and increases cAMP production upon activation (Monsma et al., 1993, Ruat et al., 1993). It is located almost exclusively within the central nervous system, with moderate to high levels in the striatum, nucleus accumbens, hippocampus, cortex, ctep and amygdala (Monsma et al., 1993, Ruat et al., 1993, Ward et al., 1995). Previous studies illustrated that several antipsychotic agents and antidepressants had high affinity for the 5-HT6 receptor and most of them were antagonists of 5-HT6 receptor (Monsma et al., 1993, Roth et al., 1994). These findings indicate that the 5-HT6 receptor might be involved in various neuropsychiatric disorders, such as anxiety, depression and schizophrenia (Hamon et al., 1999, Svenningsson et al., 2007). There are only a few studies that have explored the involvement of 5-HT6 receptor in anxiety, and the reported findings are inconsistent. Intracerebroventricular injection of 5-HT6 receptor antisense oligonucleotides suppressed the conditioned fear stress-induced 5-HT release in the rat prefrontal cortex, which may suggest an anxiolytic-like response (Yoshioka et al., 1998). Other studies indicated anxiogenic-like activity in elevated plus-maze (EPM) and social interaction tests in rats (Hamon et al., 1999, Otano et al., 1999). Furthermore, using selective ligands of the 5-HT6 receptor, several studies have found that both 5-HT6 receptor agonists and antagonists produce anxiolytic-like activities as measured by established behavioral tests in rodents (Carr et al., 2011, Nikiforuk et al., 2011, Wesolowska, 2007, Wesolowska, 2008, Wesolowska and Nikiforuk, 2007). However, the mechanisms involved in the anxiolytic-like effects of 5-HT6 receptor agonists and antagonists are still unclear. The basolateral amygdala (BLA) has been identified to play a crucial role in the regulation of anxiety-like behavior (Hale et al., 2006). There are two major cell types in the BLA, which are classified as pyramidal-like glutamate projection neurons and non-pyramidal γ-aminobutyric acid (GABA) interneurons (Carlsen, 1988, McDonald, 1992). The interneurons display extensive axonal arborization with many terminals onto the soma of the projection neurons. Therefore, they can exert powerful regulation in the firing activity of the projection neurons (Carlsen, 1988). It is reported that the amygdala exhibits significant pathological changes in PD, including atrophy and Lewy body formation (Harding et al., 2002). Electrophysiological data from our previous study illustrated that GABA interneurons in the BLA showed a more burst-firing pattern after unilateral 6-OHDA lesioning of the SNc (Sun et al., 2013). It is suggested that the BLA might participate in the modulation of anxiety-related behaviors in PD. The BLA receives 5-HT innervation arising primarily from the DRN and the BLA neurons express a moderate level of 5-HT6 receptor (Gerard et al., 1997, Ma et al., 1991, Ward et al., 1995). However, at present, there are no studies that have investigated the modulatory mechanism of the 5-HT6 receptor in the BLA on PD-associated anxiety-like behaviors.