Spindles in WAG/Rij Rats with Absence Epilepsy and Comorbid Depression

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Abstract

WAG/Rij rats are a valid model of absence epilepsy and comorbid depression. We have previously shown that WAG/Rij rats have disturbances in the sleep-wake cycle and changes in the characteristics of sleep spindles. A negative correlation was also found between the number of spike-wave discharges (SWD) and the duration of rapid eye movement (REM) sleep. Clinical evidence suggests that the traditional antidepressants imipramine and fluoxetine are effective in suppressing symptoms of depression, but may have a negative impact on the sleep-wake cycle and comorbid epilepsy in patients. Our previous studies in WAG/Rij rats showed that imipramine, when administered chronically, increases the number of SWDs, while fluoxetine at the same dose reduces their number, although both antidepressants have a pronounced antidepressant effect. Comparison of the effects of the antidepressants imipramine and fluoxetine on the sleep-wake cycle and sleep spindles in WAG/Rij rats remains unstudied. The purpose of this work is to find out: 1) what effects do imipramine and fluoxetine have on the sleep-wake cycle and the characteristics of sleep spindles in WAG/Rij rats and 2) whether there are differences in their effects. To achieve this goal, the characteristics of the sleep-wake cycle and sleep spindles were compared in WAG/Rij rats after chronic administration of antidepressants and saline and in non-epileptic Wistar rats. Administration of imipramine led to a significant decrease in the duration of REM sleep. The administration of imipramine, compared with fluoxetine, also increased the latency of the transition to sleep and the transition to REM sleep. Sleep spindle amplitude was significantly increased by both antidepressants. However, the spectral power density of “slow” and “medium” spindles, which predominate in WAG/Rij rats compared to Wistar rats, was significantly higher after administration of imipramine than fluoxetine. The results suggest that imipramine causes greater negative changes in the sleep-wake cycle and sleep spindles than fluoxetine. Studies in the WAG/Rij rat model indicate that fluoxetine is more preferable antidepressant for the treatment of depressive disorders comorbid with absence epilepsy, since it does not cause a significant deterioration in sleep quality. These results are consistent with clinical data.

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About the authors

A. V. Gabova

Institute of Higher Nervous Activity and Neurophysiology of RAS

Author for correspondence.
Email: agabova@yandex.ru
Russian Federation, Moscow

E. A. Fedosova

Institute of Higher Nervous Activity and Neurophysiology of RAS

Email: agabova@yandex.ru
Russian Federation, Moscow

K. Yu. Sarkisova

Institute of Higher Nervous Activity and Neurophysiology of RAS

Email: agabova@yandex.ru
Russian Federation, Moscow

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2. Fig. 1. Examples of passive wakefulness EEG recordings illustrating the presence of PVR in WAG/Rij rats (a) and the absence of PVR in Wistar rats (b). (a): 1 – an EEG recording of a WAG/Rij rat with a series of PVR; 2 – one of the PVR with a duration of 10 seconds is presented on an extended according to the time scale. (b): 1 – EEG of a Wistar rat without PVR; 2 – one of the fragments of an EEG recording of a Wistar rat with a duration of 10 seconds is presented on a time-extended scale.

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3. Fig. 2. Relative (%) duration of sleep-wake cycle stages in Wistar and WAG/Rij rats chronically injected with saline (Vehicle) and antidepressants fluoxetine and Imipramine. Wakefulness – wakefulness, NREM – slow wave sleep, REM – fast sleep. **p < 0.01, *p < 0.05. Horizontal lines indicate the groups being compared.

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4. Fig. 3. Duration (min) of episodes of sleep-wake cycle stages in Wistar and WAG/Rij rats chronically injected with saline and antidepressants fluoxetine and imipramine. **p < 0.01, *p < 0.05. The other symbols are as in Fig. 2.

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5. Fig. 4. The number of episodes of sleep-wake cycle stages in Wistar and WAG/Rij rats chronically injected with saline and antidepressants fluoxetine and imipramine. **p < 0.01, *p < 0.05. The other symbols are as in Fig. 2.

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6. Fig. 5. The total number of transitions from NREM sleep to other stages of sleep (Total), the number of transitions from NREM sleep to REM sleep (NREM-REM) and wakefulness (NREM-Wakefulness) in four groups of rats: Wistar rats, WAG/Rij rats, who were injected with saline, antidepressants fluoxetine and Imipramine. **p < 0.01, *p < 0.05. The other symbols are as in Fig. 2.

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7. Fig. 6. Averaged power spectra of carotid spindles in Wistar rats and WAG/Rij rats injected with saline, antidepressants fluoxetine and imipramine. The data were calculated using the Welch test method using the fast Fourier transform. The significance of the differences was determined using the Mann-Whitney U test with Bonferroni correction (312) for the number of frequencies (52) in the spectrum and the number of comparisons (8).++p < 0.01 compared with Wistar rats: with the introduction of fluoxetine at frequencies 8.5–9, 12-22.5 Hz; with the introduction of imipramine at frequencies 6-25 Hz; with the introduction of saline at frequencies 2-2.5, 5-9.5 Hz. ** p < 0.01 compared with the introduction of saline and with the introduction of imipramine on the frequencies 2-2.5, 11-11.5, 18.5–20.5.#p < 0.05, the administration of imipramine compared with the administration of fluoxetine at frequencies of 7-11 Hz.

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