Selective 5HT2A and 5HT6 Receptor Antagonists Promote Sleep in Rats

Morairty, Stephen R.; Hedley, Linda; Flores, Judith; Martin, Renée S.; Kilduff, Thomas S.

doi:10.1093/sleep/31.1.34

Cited by 105 publications

(71 citation statements)

References 34 publications

(48 reference statements)

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“…The 5-HT2A receptor antagonist volinanserin MDL 100907 (MDL) increases sleep and decreases wakefulness in rats. In addition, Morairty et al have shown that 3 different doses of MDL increase sleep in general, as well as NREM sleep and delta sleep (57). The 5-HT2A receptor indirectly controls glutamatergic signaling.…”

Section: Discussionmentioning

confidence: 99%

The impact of sleep deprivation on hippocampal-mediated learning and memory in rats

Saygın¹,

Özgüner²,

Önder³

et al. 2017

BLL

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BACKGROUND: To examine the impact of different types of sleep deprivation on hippocampal-mediated learning and memory in rats. METHODS: Forty-eight Sprague-Dawley male rats were randomly assigned to 1 of 4 equal-size groups: (1) 12 hours of sleep per day (control). (2) total sleep deprivation (TSD), (3) rapid eye movement (REM) deprivation (RD), and (4) sleep restricted to 4 hours per day (SR). All rats were subjected to swimming training in the Morris water maze (MWM). At the end of the experiments, the rats were decapitated, and hippocampus tissue was analyzed for several neurotransmitters and receptors. RESULTS: The time spent at the target quadrant increased from 20.2 to 30.0 seconds in the control group on the third day of the experiment, whereas corresponding values increased from 20.2 to 21.8 seconds in the TSD group, 22.1 to 25.4 seconds in the RD group, and 21.2 to 32.0 sec in the SR group (p = 0.026). On the seventh day of the experiment, the values decreased to 25.0 seconds in controls, 22.5 in the RD group, and 23.6 in the SR group (p = 0.045). The TSD group demonstrated signifi cant decreases in glutamate and serotonin levels compared with the control group. There was a signifi cant increase in 5-HT2 a receptor expression in all intervention groups compared with the controls. CONCLUSIONS: Our results of glutamate levels and 5-HT2a receptor expression in the hippocampus seem to be primarily involved in sleep and memory regulation (Tab. 2, Fig. 4, Ref. 59). Text in PDF www.elis.sk.

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Section: Discussionmentioning

confidence: 99%

The impact of sleep deprivation on hippocampal-mediated learning and memory in rats

Saygın¹,

Özgüner²,

Önder³

et al. 2017

BLL

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“…Rats were recorded by telemetry (10,38,39); mice were recorded either by telemetry (40) or by tethered (10,21) procedures. State determinations and data analysis were conducted as described in these publications.…”

Section: Methodsmentioning

confidence: 99%

A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity

Morairty

Dittrich

Pasumarthi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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125

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Although the neural circuitry underlying homeostatic sleep regulation is little understood, cortical neurons immunoreactive for neuronal nitric oxide synthase (nNOS) and the neurokinin-1 receptor (NK1) have been proposed to be involved in this physiological process. By systematically manipulating the durations of sleep deprivation and subsequent recovery sleep, we show that activation of cortical nNOS/NK1 neurons is directly related to non-rapid eye movement (NREM) sleep time, NREM bout duration, and EEG δ power during NREM sleep, an index of preexisting homeostatic sleep drive. Conversely, nNOS knockout mice show reduced NREM sleep time, shorter NREM bouts, and decreased power in the low δ range during NREM sleep, despite constitutively elevated sleep drive. Cortical NK1 neurons are still activated in response to sleep deprivation in these mice but, in the absence of nNOS, they are unable to up-regulate NREM δ power appropriately. These findings support the hypothesis that cortical nNOS/NK1 neurons translate homeostatic sleep drive into up-regulation of NREM δ power through an NO-dependent mechanism.T he electrical activity of the cerebral cortex has been used to distinguish sleep vs. wakefulness since the earliest EEG studies of sleep (1). Several neural circuits have been implicated in the synchronization and desynchronization of cortical activity that distinguish non-rapid eye movement sleep (NREM) from wakefulness and rapid eye movement sleep (REM). Input from the basal forebrain (BF), likely from both cholinergic and noncholinergic neurons, is critical for the desynchronized EEG characteristic of wakefulness and REM (2, 3). Synchronization of the EEG during NREM depends on thalamic as well as intrinsic cortical oscillators (4).The firing rate of cortical neurons has generally been reported to be reduced during NREM relative to wakefulness and REM (5, 6). A few studies have reported cortical neurons with the opposite pattern. For example, 4 of 177 neurons in the monkey orbitofrontal cortex increased their firing rates during NREM (7). In the cat parietal cortex, 25% of neurons discharged in phase with NREM slow waves during up states but ceased firing during quiet wakefulness (8).Using Fos immunohistochemistry as a marker of cellular activity, we described a population of cortical GABAergic interneurons that are activated during sleep in three species (9, 10). These neurons express neuronal nitric oxide synthase (nNOS) and thus likely release nitric oxide (NO) as well as GABA (11). The percentage of activated cortical nNOS neurons was proportional to NREM δ energy (NRDE), the product of NREM time and NREM EEG δ power. Because NREM time and δ power increase in response to prolonged wakefulness through a regulated process referred to as sleep homeostasis, NRDE is an electrophysiological marker of homeostatic sleep "drive." Consequently, activation of cortical nNOS neurons during sleep seems to be related to the sleep need that accrues during wakefulness.Cortical nNOS neurons receive cholinergic (12), monoamin...

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“…To monitor EEG/EMG activity, rats were implanted with sterile telemetry transmitters (F40-EET; Data Sciences, St Paul, MN) as described previously (Morairty et al, 2008(Morairty et al, , 2013 and detailed in Supplementary Materials.…”

Section: Surgical Proceduresmentioning

confidence: 99%

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

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The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wakepromoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH-or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos + cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH-and ALMtreated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL-but not in VEH-or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.

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Selective 5HT2A and 5HT6 Receptor Antagonists Promote Sleep in Rats

Abstract: These results support a role for 5-HT2A receptor modulation in NREM sleep and suggest a previously unrecognized role for 5-HT6 receptors in sleep-wake regulation.

Cited by 105 publications

References 34 publications

The impact of sleep deprivation on hippocampal-mediated learning and memory in rats

The impact of sleep deprivation on hippocampal-mediated learning and memory in rats

A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

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