Original articleComparison of platelet serotonin transporter activity in subjects with severe sleep bruxism and control
Introduction
Sleep bruxism (SB) is classified under the subgroup of sleep-related movement disorders, and at sometime in their lives, the majority of people (85–90%) experience mild or moderate symptoms thought to be a direct result of SB [1]. In severe cases, SB can cause dramatic tooth wear, which sometimes is associated with dentin hypersensitivity and tooth mobility, as well as a low prognosis of dental prostheses [2]. However, current management approaches available for SB are largely symptomatic therapies such as oral appliances and contingent counter-stimulation devices and are not considered to be curative. Therefore, a deeper understanding of the molecular mechanisms involved in SB arousals would lead to the development of new therapies for management of SB.
Recently, the central nervous system (CNS) has been hypothesized to play a role in the etiology of SB, since several clinical case reports have shown that SB frequency is alleviated and/or aggravated by administration of medications that regulate monoamine levels at the CNS. Multiple case reports have also assumed that SB events increased after selective serotonin reuptake inhibitors (SSRIs) intake [3], [4]. SSRIs are known to bind directly to serotonin transporter (SERT), which regulates pre-synaptic 5-HT levels by re-uptaking and transporting 5-HT. Consequently, SSRIs can indirectly lead to increases in the serotonin (5-HT) concentration at the synaptic cleft. Interestingly, Kishi [5] and Sabuncuoglu et al. [6] reported that administration of a selective 5-HT1A receptor agonist (tandospirone and buspirone, respectively) suppressed SSRI-induced SB activity in human patients. This clinical finding is based on the fact that the 5-HT1A receptors are located pre-synaptically and functions as a 5-HT auto-receptor; therefore, it negatively regulates the 5-HT nerve exocytosis process.
Additionally, 5-HT neurons have been reported to induce excitatory effect on the post-synaptic firing-threshold of motor nerves [7]. Inoue and colleagues examined the mechanisms by which 5-HT altered the post-synaptic firing threshold using the rat trigeminal motor nucleus [8]. They showed that 5-HT induces a dose-dependent attenuation of the medium-duration after-hyperpolarization (mAHP) amplitude through cAMP-dependent activation of protein kinase A (PKA). Based on this fact, they concluded that 5-HT could increase the firing output in jaw-closing motoneurons. Furthermore, the dorsal raphe nucleus, which contains high levels of serotonin receptors, is in close proximity to the trigeminal motor nucleus; thus, there could be a strong potential for 5-HT activation via volume transition between these nuclei. We therefore, hypothesized that serotonergic nerve functions could possibly be related to SB frequency; more specifically, that the concentration of 5-HT in the presynaptic terminal could in part regulate diurnal/nocturnal activities of trigeminal motor nerve and muscle hyperactivities (SB).
SERTs are located mainly in peripheral platelets and in the brain [9] and are encoded by a single gene located in the chromosomal region [10], and their amino acid sequences are almost identical except for a difference in post-translational modifications [11]. Nevertheless, direct and accurate investigation of alterations in 5-HT at the synapse is problematic; therefore, we utilized a peripheral platelet model which has been regarded to be comparable to central 5-HT function [12], [13].
Based on our hypothesis mentioned above, we examined the peripheral platelet SERT function as a possible indicator of the 5-HT concentration in the peripheral platelets and verified a possible association with SB frequency (high frequent bruxism and normal range subjects) in healthy young adults.
Section snippets
Study subjects
Subjects were recruited among the resident students of Okayama University Hospital in 2010. Those subjects who (1) were receiving orthodontic treatments, (2) had taken psychotropic medication within the past 6 months, (3) used an oral appliance within the past 6 months and (4) presented cutaneous diseases (i.e., atopic dermatitis) were excluded. The initial screening criterion was self-awareness of SB activities by oral interview. In order to compare subjects with high SB levels and normal
Subjects
Among the initial 39 applicants (28.0 ± 4.02 yrs, male/female: 12/27), 13 subjects fulfilled the criteria of the SB group (28.0 ± 4.68 yrs, male/female: 5/8), and 7 subjects were eligible for the NC group (30.2 ± 5.61 yrs, male/female: 3/4). The SB scores of the remaining 19 subjects fluctuated during the assessment period, and thus not included in the analyses (Fig. 1). Gender distribution, mean age showed no significant differences between the SB and NC groups (p = 0.85: Chi-squared test; p = 0.64: t-test
Discussion
This study showed that the [3H] 5-HT uptake level through SERT in the NC group was significantly greater than that in the SB group in peripheral platelets. These results suggest that SERT function analysis may provide a novel insight into the risk for SB, and that the difference of SERT activity in peripheral platelets between NC and SB individuals may help to elucidate the pathogenesis of SB severity, although further investigation is still necessary to validate and confirm the present
Conclusion
This study demonstrated a significantly higher [3H] 5-HT uptake level by SERTs in peripheral platelets of normal control subjects compared to those of severe SB subjects. These findings showed the supportive notion that demonstrates our hypothesis on the association between SB frequency and SERT activity.
Ethical approval
This experimental protocol was approved by the Ethical committee of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences (#224).
Source of funding
This research was supported by the Grant-In-Aids ((C) #20592265, (B) #23390442) for Scientific Research from Ministry of Education, Science and Culture, Japan.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
This research was supported by Grants-In-Aid ((C) #20592265, (B) #23390442) for Scientific Research from the Ministry of Education, Science and Culture of Japan.
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