Chronic Paroxetine Treatment Prevents the Emergence of Abnormal Electroencephalogram Oscillations in Huntington's Disease Mice

Kántor, Sándor; Várga, J.; Kulkarni, Shreya; Morton, A. Jennifer

doi:10.1007/s13311-017-0546-7

Cited by 12 publications

(15 citation statements)

References 57 publications

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“…The total amount of non–rapid eye movement (NREM) and rapid eye movement (REM) sleep over 24 h as well as homeostatic responses to sleep loss were not affected by the mutation (Fisher et al, 2016). In the R6/2 model, these HD-evoked changes in the EEG responded to treatment with either a serotonin uptake inhibitor (paroxetine; Kantor et al, 2017) or a hypnotic (zolpidem; Kantor et al, 2016). The circuits responsible for REM and NREM sleep are centered in the basal forebrain, lateral hypothalamus, and brainstem (Weber and Dan, 2016; Saper and Fuller, 2017; Scammell et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

et al. 2018

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Huntington's disease (HD) patients suffer from progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue. The BACHD mouse model exhibits many HD core symptoms including circadian dysfunction. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. We evaluated the effects of time-restricted feeding (TRF) on the BACHD mouse model. At 3 months of age, the animals were divided into 2 groups: ad lib and TRF. The TRF-treated BACHD mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle (ZT 15-21) of the period when mice are normally active (ZT 12-24). Following 3 months of treatment (when mice reached the early disease stage), the TRF-treated BACHD mice showed improvements in their locomotor activity and sleep behavioral rhythms. Furthermore, we found improved heart rate variability, suggesting that their autonomic nervous system dysfunction was improved. On a molecular level, TRF altered the phase but not the amplitude of the PER2::LUC rhythms measured in vivo and in vitro. Importantly, treated BACHD mice exhibited improved motor performance compared with untreated BACHD controls, and the motor improvements were correlated with improved circadian output. It is worth emphasizing that HD is a genetically caused disease with no known cure. Lifestyle changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of circadian-based treatment strategies in a preclinical model of HD.

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Section: Discussionmentioning

confidence: 99%

Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

et al. 2018

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“…The administration of the Orx receptors antagonist during the inactive behavioral period of R6/1 mice was associated with the attenuation of the power of the beta activity and the restoration of the sleep-wake cycle to some extent. Significantly, other studies have reported that a single administration of hypnotic drugs acting on the GABAergic or noradrenergic systems, or anti-depressant substances, also decreases the amplitude of the beta/gamma activity in R6/2 mice [51,52], while such data are not available in the R6/ 1 model. However, hypnotic drugs also affect other physiological brain waves that are not associated with HD pathology, such as theta activity expressed typically during REM sleep by increasing theta power and decreasing its frequency both in rodents [53] and humans [54].…”

Section: Discussionmentioning

confidence: 93%

Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington's Disease

et al. 2019

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Huntington's disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep-wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep-wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.

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“…This suggests that correcting abnormalities in the 5-HT system stabilized cortical circuits in R6/2 mice (Kantor et al, 2017). Here we found that when chronic paroxetine was started at a presymptomatic age, it allowed MASCO-driven rhythms to be induced at a time when they are not normally inducible in R6/2 mice.…”

Section: Discussionmentioning

confidence: 97%

Chronic paroxetine treatment prevents disruption of methamphetamine-sensitive circadian oscillator in a transgenic mouse model of Huntington's disease

et al. 2018

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Circadian abnormalities seen in Huntington's disease (HD) patients are recapitulated in several HD transgenic mouse models. In mice, alongside the master clock located in the suprachiasmatic nucleus (SCN), two other oscillators may influence circadian behaviour. These are the food-entrainable oscillator (FEO) and the methamphetamine-sensitive circadian oscillator (MASCO). SCN- and MASCO- (but not FEO-) driven rhythms are progressively disrupted in the R6/2 mouse model of HD. MASCO-driven rhythms are induced by chronic treatment with low dose of methamphetamine and characterised by an increase in period length to greater than 24 h. Interestingly, the rhythms mediated by MASCO deteriorate earlier than those mediated by the SCN in R6/2 mice. Here, we used a pharmacological strategy to investigate the mechanisms underlying MASCO-driven rhythms in WT mice. In contrast to methamphetamine, chronic cocaine was ineffective in generating a MASCO-like component of activity although it markedly increased locomotion. Furthermore, neither blocking dopamine (DA) receptors (with the DA antagonist haloperidol) nor blocking neurotransmission by inhibiting the activity of vesicular monoamine transporter (with reserpine) prevented the expression of the MASCO-driven rhythms, although both treatments downregulated locomotor activity. Interestingly, chronic treatment with paroxetine, a serotonin-specific reuptake inhibitor commonly used as antidepressant in HD, was able to restore the expression of MASCO-driven rhythms in R6/2 mice. Thus, MASCO-driven rhythms appear to be mediated by both serotoninergic and dopaminergic systems. This supports the idea that abnormalities in MASCO output may contribute to both the HD circadian and psychiatric phenotype.

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Chronic Paroxetine Treatment Prevents the Emergence of Abnormal Electroencephalogram Oscillations in Huntington's Disease Mice

Cited by 12 publications

References 57 publications

Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington's Disease

Chronic paroxetine treatment prevents disruption of methamphetamine-sensitive circadian oscillator in a transgenic mouse model of Huntington's disease

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