RESUMEN

Brain oscillations in the gamma frequency band of the electroencephalogram (EEG) have been implicated in several sensory and cognitive processes, and have also been associated with numerous neuropsychiatric disorders, including depression. The widely prescribed selective serotonin reuptake inhibitors (SSRIs), similarly to other antidepressants, are known to produce markedly different effects on sleep and behavioral measures with acute and chronic administration. Although there are studies examining the acute effect of escitalopram on slower (<30 Hz) oscillations, we hardly could find any data about the effect of the drug on higher-frequency EEG oscillations (>30 Hz) in different sleep-wake stages, particularly comparing the acute and chronic effects of the drug concerning gamma oscillations. Our aim was to investigate, how escitalopram affects gamma power in different sleep-wake stages, and to discover possible differential effects between acute and chronic treatment. EEG-equipped Wistar rats were treated with escitalopram or vehicle acutely (10 mg/kg, i.p.) or chronically (10 mg/kg/day for 21 days, osmotic minipumps) and frontoparietal EEG, electromyogram and motor activity were recorded during the first 3 h of passive phase. We found that acute and chronic escitalopram treatment affected gamma oscillations differently. While acute escitalopram caused a reduction in gamma power during rapid eye movement sleep (REMS) and intermediate stage of sleep (IS), chronic treatment caused an elevation in gamma power during non-REMS stages, namely in light and deep slow-wave sleep (SWS-1 and SWS-2, respectively) and in IS. However, gamma activity during active and passive wakefulness (AW and PW, respectively) was not influenced by either acute or chronic dosing of escitalopram. Furthermore, we found that in drug-free (vehicle-treated) rats, a relatively high gamma power was present during wakefulness and REMS, while a much lower power was measured during non-REMS stages. These findings indicate that acute and chronic administration of escitalopram alter gamma activity differently, moreover, in a sleep-wake stage dependent manner that may be related to differential therapeutic and/or side effects.

Asunto(s)

Antidepresivos/administración & dosificación , Citalopram/administración & dosificación , Electroencefalografía/efectos de los fármacos , Fases del Sueño/efectos de los fármacos , Animales , Esquema de Medicación , Electromiografía , Masculino , Ratas Wistar

RESUMEN

BACKGROUND: Shortened rapid eye movement (REM) sleep latency and increased REM sleep amount are presumed biological markers of depression. These sleep alterations are also observable in several animal models of depression as well as during the rebound sleep after selective REM sleep deprivation (RD). Furthermore, REM sleep fragmentation is typically associated with stress procedures and anxiety. The selective serotonin reuptake inhibitor (SSRI) antidepressants reduce REM sleep time and increase REM latency after acute dosing in normal condition and even during REM rebound following RD. However, their therapeutic outcome evolves only after weeks of treatment, and the effects of chronic treatment in REM-deprived animals have not been studied yet. RESULTS: Chronic escitalopram- (10 mg/kg/day, osmotic minipump for 24 days) or vehicle-treated rats were subjected to a 3-day-long RD on day 21 using the flower pot procedure or kept in home cage. On day 24, fronto-parietal electroencephalogram, electromyogram and motility were recorded in the first 2 h of the passive phase. The observed sleep patterns were characterized applying standard sleep metrics, by modelling the transitions between sleep phases using Markov chains and by spectral analysis. Based on Markov chain analysis, chronic escitalopram treatment attenuated the REM sleep fragmentation [accelerated transition rates between REM and non-REM (NREM) stages, decreased REM sleep residence time between two transitions] during the rebound sleep. Additionally, the antidepressant avoided the frequent awakenings during the first 30 min of recovery period. The spectral analysis showed that the SSRI prevented the RD-caused elevation in theta (5-9 Hz) power during slow-wave sleep. Conversely, based on the aggregate sleep metrics, escitalopram had only moderate effects and it did not significantly attenuate the REM rebound after RD. CONCLUSION: In conclusion, chronic SSRI treatment is capable of reducing several effects on sleep which might be the consequence of the sub-chronic stress caused by the flower pot method. These data might support the antidepressant activity of SSRIs, and may allude that investigating the rebound period following the flower pot protocol could be useful to detect antidepressant drug response. Markov analysis is a suitable method to study the sleep pattern.

Asunto(s)

Encéfalo/efectos de los fármacos , Citalopram/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Privación de Sueño/fisiopatología , Sueño REM/efectos de los fármacos , Animales , Encéfalo/fisiopatología , Catéteres de Permanencia , Electrodos Implantados , Electroencefalografía , Masculino , Cadenas de Markov , Modelos Neurológicos , Polisomnografía , Distribución Aleatoria , Ratas Wistar , Sueño REM/fisiología , Ritmo Teta/efectos de los fármacos

RESUMEN

Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5-9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation.

Asunto(s)

Adaptación Fisiológica/efectos de los fármacos , Aminopiridinas/farmacología , Citalopram/farmacología , Indoles/farmacología , Antagonistas de la Serotonina/farmacología , Sueño REM/efectos de los fármacos , Ritmo Teta/efectos de los fármacos , Vigilia/efectos de los fármacos , Análisis de Varianza , Animales , Electroencefalografía , Electromiografía , Análisis de Fourier , Masculino , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina

RESUMEN

STUDY OBJECTIVES: Millions suffer from sleep disorders that often accompany severe illnesses such as major depression; a leading psychiatric disorder characterized by appetite and rapid eye movement sleep (REMS) abnormalities. Melanin-concentrating hormone (MCH) and nesfatin-1/NUCB2 (nesfatin) are strongly co - expressed in the hypothalamus and are involved both in food intake regulation and depression. Since MCH was recognized earlier as a hypnogenic factor, we analyzed the potential role of nesfatin on vigilance. DESIGN: We subjected rats to a 72 h-long REMS deprivation using the classic flower pot method, followed by a 3 h-long 'rebound sleep'. Nesfatin mRNA and protein expressions as well as neuronal activity (Fos) were measured by quantitative in situ hybridization technique, ELISA and immunohistochemistry, respectively, in 'deprived' and 'rebound' groups, relative to controls sacrificed at the same time. We also analyzed electroencephalogram of rats treated by intracerebroventricularly administered nesfatin-1, or saline. RESULTS: REMS deprivation downregulated the expression of nesfatin (mRNA and protein), however, enhanced REMS during 'rebound' reversed this to control levels. Additionally, increased transcriptional activity (Fos) was demonstrated in nesfatin neurons during 'rebound'. Centrally administered nesfatin-1 at light on reduced REMS and intermediate stage of sleep, while increased passive wake for several hours and also caused a short-term increase in light slow wave sleep. CONCLUSIONS: The data designate nesfatin as a potential new factor in sleep regulation, which fact can also be relevant in the better understanding of the role of nesfatin in the pathomechanism of depression.

Asunto(s)

Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/farmacología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/farmacología , Hipotálamo/efectos de los fármacos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/farmacología , Sueño REM/efectos de los fármacos , Vigilia/efectos de los fármacos , Animales , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al ADN/metabolismo , Electroencefalografía , Expresión Génica/efectos de los fármacos , Hipotálamo/fisiología , Inyecciones Intraventriculares , Masculino , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Nucleobindinas , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Sueño REM/fisiología , Vigilia/fisiología

RESUMEN

RATIONALE: Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ("flower pot") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. OBJECTIVES: We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons. METHODS: Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long "rebound sleep", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. RESULTS: During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. CONCLUSIONS: These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders.

Asunto(s)

Citalopram/farmacología , Hormonas Hipotalámicas/metabolismo , Hipotálamo/efectos de los fármacos , Melaninas/metabolismo , Neuronas/efectos de los fármacos , Hormonas Hipofisarias/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sueño REM/efectos de los fármacos , Animales , Citalopram/administración & dosificación , Electroencefalografía , Hipotálamo/metabolismo , Hipotálamo/fisiopatología , Masculino , Neuronas/metabolismo , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Factores de Tiempo

RESUMEN

The effects of the widely used selective serotonin reuptake inhibitor (SSRI) antidepressants on sleep have been intensively investigated. However, only a few animal studies examined the effect of escitalopram, the more potent S-enantiomer of citalopram, and conclusions of these studies on sleep architecture are limited due to the experimental design. Here, we investigate the acute (2 and 10 mg/kg, i.p. injected at the beginning of the passive phase) or chronic (10 mg/kg/day for 21 days, by osmotic minipumps) effects of escitalopram on the sleep and quantitative electroencephalogram (EEG) of Wistar rats. The first 3 h of EEG recording was analyzed at the beginning of passive phase, immediately after injections. The acutely injected 2 and 10 mg/kg and the chronically administered 10 mg/kg/day escitalopram caused an approximately three, six and twofold increases in rapid eye movement sleep (REMS) latency, respectively. Acute 2-mg/kg escitalopram reduced REMS, but increased intermediate stage of sleep (IS) while the 10 mg/kg reduced both. We also observed some increase in light slow wave sleep and passive wake parallel with a decrease in deep slow wave sleep and theta power in both active wake and REMS after acute dosing. Following chronic treatment, only the increase in REMS latency remained significant compared to control animals. In conclusion, adaptive changes in the effects of escitalopram, which occur after 3 weeks of treatment, suggest desensitization in the function of 5-HT(1A) and 5-HT(1B) receptors.

Asunto(s)

Adaptación Fisiológica/efectos de los fármacos , Citalopram/farmacología , Movimientos Oculares/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sueño REM/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Electroencefalografía , Electromiografía , Masculino , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Ritmo Teta/efectos de los fármacos , Factores de Tiempo , Vigilia/efectos de los fármacos

RESUMEN

Rapid eye movement (REM) sleep rebound following REM deprivation using the platform-on-water method is characterized by increased time spent in REM sleep and activation of melanin-concentrating hormone (MCH) expressing neurons. Orexinergic neurons discharge reciprocally to MCH-ergic neurons across the sleep-wake cycle. However, the relation between REM architecture and the aforementioned neuropeptides remained unclear. MCH-ergic neurons can be divided into two subpopulations regarding their cocaine- and amphetamine-regulated transcript (CART) immunoreactivity, and among them the activation of CART-immunoreactive subpopulation is higher during the REM rebound. However, the possible role of stress in this association has not been elucidated. Our aims were to analyze the relationship between the architecture of REM rebound and the activation of hypothalamic MCH-ergic and orexinergic neurons. We also intended to separate the effect of stress and REM deprivation on the subsequent activation of subpopulations of MCH-ergic neurons. In order to detect neuronal activity, we performed MCH/cFos and orexin/cFos double immunohistochemistry on home cage, sleep deprived and sleep-rebound rats using the platform-on-water method with small and large (stress control) platforms. Furthermore, REM architecture was analyzed and a triple MCH/CART/cFos immunohistochemistry was also performed on the rebound groups in the same animals. We found that the activity of MCH- and orexin-immunoreactive neurons during REM rebound was positively and negatively correlated with the number of REM bouts, respectively. A negative reciprocal correlation was also found between the activation of MCH- and orexin-immunoreactive neurons during REM rebound. Furthermore, difference between the activation of CART-immunoreactive (CART-IR) and non-CART-immunoreactive MCH-ergic neuron subpopulations was found only after selective REM deprivation, it was absent in the large platform (stress control) rebound group. These results support the role of CART-IR subpopulation of MCH-ergic neurons and the inverse relationship of MCH and orexin in the regulation of REM sleep after REM sleep deprivation.

Asunto(s)

Hormonas Hipotalámicas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Melaninas/metabolismo , Neuronas/fisiología , Neuropéptidos/metabolismo , Hormonas Hipofisarias/metabolismo , Privación de Sueño/metabolismo , Fases del Sueño/fisiología , Sueño REM/fisiología , Animales , Nivel de Alerta/fisiología , Electroencefalografía , Electromiografía , Fenómenos Electrofisiológicos , Hipotálamo/metabolismo , Inmunohistoquímica , Masculino , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Orexinas , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar

RESUMEN

The recreational drug "Ecstasy" [3,4-methylenedioxymethamphetamine (MDMA)] has a well-characterised neurotoxic effect on the 5-hydroxytryptamine (5-HT) neurons in animals. Despite intensive studies, the long-term functional consequencies of the 5-HT neurodegeneration remains elusive. The aim of this study was to investigate whether any alteration of 5-hydroxytryptamine-3 (5-HT(3)) receptor functions on the sleep-wake cycle, motor activity, and quantitative EEG could be detected 6 months after a single dose of 15 mg/kg of MDMA. The selective 5-HT(3) receptor agonist m-chlorophenylbiguanide (mCPBG; 1 mg/kg, i.p.) or vehicle was administered to freely moving rats pre-treated with MDMA (15 mg/kg, i.p.) or vehicle 6 months earlier. Polysomnographic and motor activity recordings were performed. Active wake (AW), passive wake (PW), light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2), and paradoxical sleep were classified. In addition, EEG power spectra were calculated for the second hour after mCPBG treatment for each stage. AW increased and SWS-1 decreased in the second hour after mCPBG treatment in control animals. mCPBG caused significant changes in the EEG power in states with cortical activation (AW, PW, paradoxical sleep). In addition, mCPBG had a biphasic effect on hippocampal theta power in AW with a decrease in 7 Hz and a stage-selective increase in the upper range (8-9 Hz). Effects of mCPBG on the time spent in AW and SWS-1 were eliminated or reduced in MDMA-treated animals. In addition, mCPBG did not increase the upper theta power of AW in rats pre-treated with MDMA. These data suggest long-term changes in 5-HT(3) receptor function after MDMA.

Asunto(s)

Encéfalo/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Actividad Motora/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Receptores de Serotonina 5-HT3/metabolismo , Serotoninérgicos/farmacología , Animales , Biguanidas/farmacología , Encéfalo/fisiología , Ritmo Circadiano/fisiología , Electroencefalografía , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Actividad Motora/fisiología , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Polisomnografía , Distribución Aleatoria , Ratas , Agonistas del Receptor de Serotonina 5-HT3 , Serotoninérgicos/administración & dosificación , Agonistas de Receptores de Serotonina/farmacología , Sueño/efectos de los fármacos , Sueño/fisiología , Fases del Sueño/efectos de los fármacos , Fases del Sueño/fisiología , Ritmo Teta , Factores de Tiempo , Vigilia/efectos de los fármacos , Vigilia/fisiología

RESUMEN

The single platform-on-water (flower pot) method is extensively used for depriving rapid eye movement sleep (REMS). Detailed comparison of sleep-wake architecture, recorded during the rebound period after spending three days on either a small or large platform, could separate the effects of REMS deficit from other stress factors caused by the procedure. A further aim of the study was to find the most characteristic REMS parameter of the rebound originating from REMS deficit. Rats were kept on a small or large platform for 72 h. Their fronto-parietal electroencephalogram, electromyogram and motility were recorded during the 24 h rebound at the beginning of the passive phase. A similar period of a home cage group was also recorded. The most typical differences between the two rebound groups were the increased cumulative time and longer average duration of REMS episodes without significant change in the number of these episodes of the small platform animals during the passive phase. Results obtained by cosinor analysis were in accordance with the findings above. Since we did not find any difference in the average duration of REMS episodes comparing the large platform rebound group and the home cage group, we concluded that the increased mean duration of REMS episodes is a selective marker for the rebound caused by small platform sleep deprivation, while other changes in sleep architecture may be the consequence of stress and also some sleep deficit.

Asunto(s)

Privación de Sueño/fisiopatología , Sueño REM/fisiología , Animales , Ritmo Circadiano/fisiología , Electrodos Implantados , Electroencefalografía , Electromiografía , Lóbulo Frontal/fisiopatología , Masculino , Lóbulo Parietal/fisiopatología , Polisomnografía , Distribución Aleatoria , Ratas , Ratas Wistar , Sueño/fisiología , Fases del Sueño/fisiología , Factores de Tiempo , Vigilia/fisiología

RESUMEN

OBJECTIVE: The cyclic variation of physical and psychological phenomena has been accepted as a natural consequence of the cyclicity of the human female reproductive function. The exact nature of these changes, however, has not been fully understood. The aim of our study was to investigate the fluctuation of psychological and physical symptoms throughout the female reproductive cycle in healthy, non-PMDD women. METHOD: 63 psychiatrically healthy, non-PMDD women with normal regular menstrual cycles and not using hormonal contraceptive methods participated in the study. Participants completed the PRISM calendar every night for three consecutive cycles and on three predefined days of the first cycle they completed several other psychometric measures (SCL-51, STAI, ZSDS, EAT and Mind and Body Cathexis Scale). Based on an at least 66% increase in physical symptoms from the late follicular to the late luteal phase on the PRISM, subjects were assigned to LPPS (luteal phase physical symptoms) and nonLPPS (no luteal phase physical symptoms) groups. Average of psychometric scores obtained at the three predefined days were compared between the two groups. RESULTS: There was a significant difference between the two groups only in case of the interpersonal sensitivity subscale of the SCL-51. CONCLUSION: Our results indicate that the appearance of severe physical symptoms in the late luteal phase of the female reproductive cycle is not accompanied by a worsening of psychological symptoms. The appearance of enhanced psychological symptomatology attributed to the luteal phase of the female reproductive cycle thus seems to be independent of the appearance of severe physical symptoms.

Asunto(s)

Afecto , Ciclo Menstrual/psicología , Síndrome Premenstrual/psicología , Adulto , Ansiedad/etiología , Conducta Compulsiva/etiología , Depresión/etiología , Femenino , Fase Folicular/psicología , Humanos , Relaciones Interpersonales , Menstruación/psicología , Conducta Obsesiva/etiología , Síndrome Premenstrual/fisiopatología , Psicometría , Índice de Severidad de la Enfermedad , Trastornos Somatomorfos/etiología , Encuestas y Cuestionarios , Adulto Joven