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  • Currently the precise nature of augmentation is not fully un

    2018-11-15

    Currently, the precise nature of augmentation is not fully understood. What is known is that it is caused by a disturbance of the dopaminergic system [5]. It is believed that the increased dopaminergic state is caused by excessive stimulation of D1 compared with D2 receptors, which leads to decreased sensitivity and a down-regulation of the D1 receptor. It is also believed that this hyper-dopaminergic state leads to a supersensitivity of the dopamine receptor, similar to a mechanism proposed for tardive dyskinesia. Another theoretical possibility based on excessive orexinergic stimulation states that this stimulation would lead to a hyper-motor syndrome via the large projections of orexinergic neurons to the monoaminergic system and the anterior horn JAK STAT Compound Library of the spinal cord [4]. Using PET, Cervenka et al. [17] demonstrated increased availability of D2 receptors in patients with RLS. This interpretation is consistent with the dopaminergic neurotransmission hypothesis in RLS, wherein the increased concentration of receptors may be due to the positive regulation of the receptor in response to low concentrations of dopamine. Interestingly, sustained treatment with PPX (which over stimulates somatodendritic D2/D3 receptors) can lead to a decrease in D2/D3 receptor responsiveness and a subsequent restoration of the mean firing rate of DA neurons [7]. The present study showed no significant difference in D2-like receptor expression due to long-term PPX administration (71 days). However, it is known that continuous stimulation during treatment down-regulates the number of receptors, and, by analyzing Fig. 3, there seems to be a tendency for a reduction of D2 receptor expression. This finding is consistent with results previously reported by Chernoloz et al. [7] that demonstrated a decreased sensitivity and density of D2-like receptors following chronic administration of the D2-like agonist PPX Studies have shown that the development of regular locomotion, requires a synergistic interaction between the dopaminergics D1 and D2 [18] or D1 and D3 receptors [19,20]. However, activation of the postsynaptic D2 receptors can increase locomotion. In the hyper-dopaminergic phase of RLS treatment, hyper-excitability of the dopaminergic system leads to a reduction of the flexor reflexes and an initial increase of the delayed flexor reflexes [5]. This result was also confirmed in the present study because during the initial phase of the PPX treatment, the rats showed a significant reduction in locomotion and a substantial increase in immobilization. Thus, for future studies, it is important consider experiments using spontaneously hypertensive rats, an animal model of RLS previously reported by Esteves et al., [21], to investigate the underlying pathophysiology of augmentation.
    Conflict of interest
    Acknowledgments This work was supported by grants from Associação Fundo de Incentivo à Pesquisa (AFIP), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2011/12540-4 to WAOA and CEPID No. 98/14303-3 to ST). The authors thank the Centro de Estudos em Psicobiologia e Exercício (CEPE) and Centro de Estudos Multidisciplinar em Sonolência e Acidentes (CEMSA). ST and MTM are recipients of the CNPq fellowship.
    Background The World Health Organization (WHO) has documented seven categories of adverse health and social effects of noise pollution, whether occupational, social or environmental: hearing impairment, interference with spoken communication, cardiovascular disturbances, mental health problems, impaired cognition, negative social behaviors and sleep disturbances [1]. The latter is considered the most deleterious non-auditory effect because of its impact on quality of life and daytime performance [2–4]. Environmental noise, especially that caused by transportation means, is a growing problem in our modern cities [5]. It is considered a major cause of exogenous sleep disturbances, after somatic problems and day tensions [6,7].