Pablo Torterolo

Auditory deprivation modifies sleep in the guinea-pig

After destruction of both cochleae, a significant enhancement of both paradoxical sleep and slow wave sleep together with decreased wakefulness, were observed for up to 45 days. The sleep augmentation consisted of an increment in the number of episodes of both slow wave and paradoxical sleep rather than in the duration of single episodes. The partial isolation provoked by deafness is postulated as explanation. We suggest that the suppression of one input to a complex set of networks related to the sleep-waking cycle, introduce an imbalance that leads to sleep enhancement.

Immunoneutralization of melanin-concentrating hormone (MCH) in the dorsal raphe nucleus: effects on sleep and wakefulness.

Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator exert a positive control over energy homeostasis, inducing feeding and decreasing metabolism. Recent studies have shown also that this system plays a role in the generation and/or maintenance of sleep. MCHergic neurons project to the serotonergic dorsal raphe nucleus (DR), a neuroanatomical structure involved in several functions during wakefulness (W), and in the regulation of rapid-eye movements (REM) sleep. Recently, we determined the effect of MCH microinjected into the DR on sleep variables in the rat. MCH produced a marked increment of REM sleep, whereas slow wave sleep (SWS) showed only a moderate increase. In the present study, we analyze the effect of immunoneutralization of MCH in the DR on sleep and W in the rat. Compared to the control solution, microinjections of anti-MCH antibodies (1/100 solution in 0.2 μl) induced a significant increase in REM sleep latency (31.2±7.1 vs. 84.2±24.8 min, p<0.05) and a decrease of REM sleep time (37.8±5.4 vs. 17.8±2.9 min, p<0.05) that was related to the reduction in the number of REM sleep episodes. In addition, there was an increase of total W time (49.8±4.6 vs. 72.0±5.7 min, p<0.01). Light sleep and SWS remained unchanged. The intra-DR administration of a more diluted solution of anti-MCH antibodies (1/500) or rabbit pre-immune serum did not modify neither W nor REM sleep variables. Our findings strongly suggest that MCH released in the DR facilitates the occurrence of REM sleep.

Microinjection of the melanin-concentrating hormone into the sublaterodorsal tegmental nucleus inhibits REM sleep in the rat.

A study was performed on the effects of local microinjection of melanin-concentrating hormone (MCH) into the right sublaterodorsal tegmental nucleus (SLD) on sleep and wakefulness in rats prepared for chronic sleep recordings. MCH 200ng significantly decreased rapid-eye-movement sleep (REMS) time during the first and second 2-h of the recording period which was related to the reduction of the number of REMS periods and the increase of REMS latency. It is proposed that REMS inhibition was related to the direct deactivation of SLD glutamatergic neurons by the peptide.

The Involvement of 5-HT 2A Receptor in the Regulation of Sleep and Wakefulness, and the Potential Therapeutic Use of Selective 5-HT 2A Receptor Antagonists and Inverse Agonists for the Treatment of an Insomnia Disorder

Several agents have been shown to improve sleep induction and/or maintenance in patients with primary or comorbid insomnia. These include benzodiazepine and non-benzodiazepine receptor allosteric modulators, melatonin and the melatonin receptor agonist ramelteon, low dose doxepin, and suvorexant. However, benzodiazepines induce a further reduction of N3 sleep [slow wave sleep (SWS) or delta sleep] and rapid-eye-movement sleep (REMS), whereas values corresponding to these variables remain decreased during non-benzodiazepine, melatonin, ramelteon or low-dose doxepin administration. By contrast, suvorexant increases REMS. There is evidence indicating that non-selective (ritanserin, ketanserin, sertindole, ICI-170809, ICI-169369, RP-62203, SR-46349B) and selective (volinanserin, pruvanserin, eplivanserin) 5-HT2A receptor antagonists, as well as 5-HT2A receptor inverse agonists (nelotanserin, pimavanserin) increase SWS in laboratory animals and N3 sleep in subjects with normal sleep and/or patients with an insomnia disorder. Thus, the association of a selective 5-HT2A receptor antagonist or a 5-HT2A receptor inverse agonist with a hypnotic drug could be a valid alternative to normalize N3 sleep in patients with an insomnia complaint.

Distribution of MCH-containing fibers in the feline brainstem: Relevance for REM sleep regulation

HighlightsMCH plays a critical role in the control of REM sleep.The distribution of MCH+ fibers in the brainstem of the cat was analyzed.High density of MCHergic fibers was found in REM sleep controlling areas.MCH‐IR cells were found in the pontine reticular formation. ABSTRACT Neurons that utilize melanin‐concentrating hormone (MCH) as a neuromodulator are localized in the postero‐lateral hypothalamus and incerto‐hypothalamic area. These neurons project diffusely throughout the central nervous system and have been implicated in critical physiological processes, such as sleep. Unlike rodents, in the order carnivora as well as in humans, MCH exerts its biological functions through two receptors: MCHR‐1 and MCHR‐2. Hence, the cat is an optimal animal to model MCHergic functions in humans. In the present study, we examined the distribution of MCH‐positive fibers in the brainstem of the cat. MCHergic axons with distinctive varicosities and boutons were heterogeneously distributed, exhibiting different densities in distinct regions of the brainstem. High density of MCHergic fibers was found in the dorsal raphe nucleus, the laterodorsal tegmental nucleus, the periaqueductal gray, the pendunculopontine tegmental nucleus, the locus coeruleus and the prepositus hypoglossi. Because these areas are involved in the control of REM sleep, the present anatomical data support the role of this neuropeptidergic system in the control of this behavioral state.

The Effects of Melanin-Concentrating Hormone on Neurotransmitter Systems Involved in the Generation and Maintenance of Wakefulness

Within the central nervous system (CNS), melanin-concentrating hormone (MCH) participates in a number of functions including sleep-wake behavior. In this respect, MCHergic neurons project widely throughout the central nervous system (CNS) to neural structures involved in the regulation of wakefulness (W). An enhancement of REM sleep time has been described following the microinjection of MCH into the dorsal raphe nucleus (serotonergic neurons), locus coeruleus nucleus (noradrenergic neurons), and basal forebrain [(horizontal limb of the diagonal band of Broca) glutamatergic and cholinergic (W-on) neurons] of rodents. In addition, optogenetic stimulation of MCH terminals in the tuberomammillary nucleus (histaminergic neurons) is followed by an increase in the duration of REM sleep episodes. Moreover, the finding that the neuropeptide negatively modulates the mesolimbic dopaminergic function tends to indicate that the inhibition of nucleus accumbens and ventral tegmental nucleus dopaminergic neurons by MCH could facilitate the occurrence of REM sleep. Thus, the REM sleep-inducing and sleep-facilitating effect of MCH is at least partly related to the deactivation of monoaminergic, glutamatergic, and cholinergic (W-on) neurons.

Melanin-Concentrating Hormone in Medical Conditions

In the last decade, there was an impressive advance in the knowledge of the anatomy and physiology of the melanin-concentrating hormone (MCH) neuronal system. However, its role in pathology is still not clear. MCH is a peptidergic neuromodulator synthesized by neurons whose somas are mainly located in the posterolateral hypothalamus and incerto-hypothalamic area. The MCHergic neurons project throughout the central nervous system innervating areas involved in several physiological functions. MCH exerts its biological effects acting through two metabotropic receptors. There are substantive experimental data suggesting that the MCHergic system is involved in the control of energy homeostasis, mood, and sleep. In the present study, we summarize data related to the role of MCH in these functions, as well as preclinical and clinical evidences showing that dysfunction of the MCHergic system might be involved in several medical disorders including obesity, central hypersomnia, mood disorders, and ciliopathies.

Melanin-Concentrating Hormone: Role in Nursing and Sleep in Mother Rats

In mammals, the postpartum female undergoes the most important physiological and behavioral changes in life, which allow orchestrating two essential behaviors for survival: nursing and sleep. Although the melanin-concentrating hormone (MCH) is mainly found within the posterolateral hypothalamus and incerto-hypothalamic area, during lactation this neuropeptide is also expressed in the preoptic area (POA). Remarkably, this brain area controls key components not only of the maternal behavior repertoire but also is involved in the regulation of sleep and wakefulness. In this sense, when MCH is microinjected into the POA, this neuropeptide is capable to reduce the motivational aspects of maternal behavior in postpartum rats while increases sleep in male rats. This effect seems to oppose to one of the dopaminergic systems that promotes wakefulness while in postpartum rats stimulates motivational components of maternal behavior. How the MCHergic system controls maternal behavior and sleep within the POA is still an unresolved question.

MCH and Depression

Depression is a mood disorder affecting emotional, somatic, and cognitive domains. The efficacy of the antidepressant therapies is generally acceptable; however, unpleasant or adverse effects, delayed onset of action, and unresponsive patients continue to be the most common problem in the psychiatric practice. Under these circumstances, the recent implication of the hypothalamic neuropeptide melanin-concentrating hormone (MCH) in the regulation of emotion and mood has offered a great opportunity to study this neuropeptidergic system in the neural bases of depression and its treatment.

Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile

Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.