Reduced Levels of Serotonin 2A Receptors Underlie Resistance of Egr3-Deficient Mice to Locomotor Suppression by Clozapine

Williams, Alison A.; Ingram, Wendy Marie; Levine, Sarah; Resnik, Jack; Kamel, Christy M.; Lish, James R.; Elizalde, Diana I.; Janowski, Scott A; Shoker, Joseph; Kozlenkov, Alexey; González-Maeso, Javier; Gallitano, Amelia L.

doi:10.1038/npp.2012.81

Cited by 36 publications

(44 citation statements)

References 69 publications

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“…These parallels indicate that 5-HT2A deficits may play an important role in the behavioral 11,16 and sleep phenotypes demonstrated in Egr3-deficient mice. Yet, there is one key difference between Egr3-/-and 5-HT2A-/-mice in sleep regulation.…”

Section: During Sleep Disruptionmentioning

confidence: 70%

“…These findings are in line with prior studies in Egr3-deficient mice showing resistance to locomotor suppression to similar pharmacological treatment. 11,16 In WT mice, clozapine caused sedation as reported in rats 24 and blockade of the 5-HT2 receptors produced a prolonged inhibition of AW and low-frequency activity. These effects were not detected in Egr3-/-mice.…”

Section: During Sleep Disruptionmentioning

confidence: 83%

“…11,16 This effect is shown to be mediated, at least in part, by 5-HT2A receptors, 11 and 5-HT2A receptor-deficient mice display the same phenotype. 17 If Egr3 modulates the expression of plasticity-associated genes and serotonergic signaling in a physiologically relevant manner, it may be essential for waking behavior, sleep timing, and the electroencephalographic manifestations of sleep need.…”

Section: Significancementioning

confidence: 99%

“…9,10 There are no gross abnormalities in brain development, basal synaptic transmission, or density of hippocampal neurons. 9 However, Egr3-deficiency results in a 70% reduction in cortical serotonin 5-HT2A receptor binding compared to wild-type (WT) mice 11 and abolishes…”

Section: Introductionmentioning

confidence: 99%

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Sleep Homeostatic and Waking Behavioral Phenotypes inEgr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits

Grønli

Clegern

Schmidt

et al. 2016

Sleep

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Study Objective: The expression of the immediate early gene early growth response 3 (Egr3) is a functional marker of brain activity including responses to novelty, sustained wakefulness, and sleep. We examined the role of this gene in regulating wakefulness and sleep. Methods: Electroencephalogram/electromyogram (EEG/EMG) were recorded in Egr3-/-and wild-type (WT) mice during 24 h baseline, 6 h sleep disruption and 6 h recovery. Serotonergic signaling was assessed with 6 h EEG/EMG recordings after injections of nonselective 5-HT2 antagonist (clozapine), selective 5-HT2 antagonists (5-HT2A; MDL100907 and 5-HT2BC; SB206553) and a cocktail of both selective antagonists, administered in a randomized order to each animal. Results: Egr3-/-mice did not exhibit abnormalities in the timing of wakefulness and slow wave sleep (SWS); however, EEG dynamics in SWS (suppressed 1-3 Hz power) and in quiet wakefulness (elevated 3-8 Hz and 15-35 Hz power) differed in comparison to WT-mice. Egr3-/-mice showed an exaggerated response to sleep disruption as measured by active wakefulness, but with a blunted increase in homeostatic sleep drive (elevated 1-4 Hz power) relative to WT-mice. Egr3-/-mice exhibit greatly reduced sedative effects of clozapine at the electroencephalographic level. In addition, clozapine induced a previously undescribed dissociated state (low amplitude, low frequency EEG and a stable, low muscle tone) lasting up to 2 h in WT-mice. Egr3-/-mice did not exhibit this phenomenon. Selective 5-HT2A antagonist, alone or in combination with selective 5-HT2BC antagonist, caused EEG slowing coincident with behavioral quiescence in WT-mice but not in Egr3-/-mice. Conclusion: Egr3 has an essential role in regulating cortical arousal, wakefulness, and sleep, presumably by its regulation of 5-HT2 receptors.

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Section: During Sleep Disruptionmentioning

confidence: 70%

Section: During Sleep Disruptionmentioning

confidence: 83%

Section: Significancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sleep Homeostatic and Waking Behavioral Phenotypes inEgr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits

Grønli

Clegern

Schmidt

et al. 2016

Sleep

View full text Add to dashboard Cite

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“…58,80−83 Recent findings suggest that the 5-HT 2A receptor is involved in the locomotor suppressive effects of clozapine. 84,85 Prepulse Inhibition of Startle. Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that refers to the reduction in the startle response produced by a low-intensity nonstartling stimulus (the prepulse) presented shortly before the startle stimulus.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

Animal Models of Serotonergic Psychedelics

Hanks

González-Maeso

2012

ACS Chem. Neurosci.

Self Cite

126

112

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The serotonin 5-HT 2A receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.KEYWORDS: Psychedelic, hallucinogenic, schizophrenia, psychosis, serotonin 5-HT 2A receptor, G protein-coupled receptor (GPCR), lysergic acid diethylamide (LSD), mouse behavior models E lucidating the mechanisms by which psychedelics induce their unique neuropsychological effects has important implications for a better understanding of behavioral processes such as cognition, perception, emotion, and sense of self. 1−5 The term psychedelic was coined in 1957 by the British psychiatrist Humphry Osmond to describe the effects of psychoactive drugs such as psilocybin, mescaline, and lysergic acid diethylamide (LSD). 6 These drugs belong to a larger group of substances known as hallucinogens, which also includes dissociatives (e.g., ketamine and phencyclidine), and deliriants (e.g., scopolamine and atropine), as well as compounds such as salvinorin A. Psychedelics all behave as agonists or partial agonists at the serotonin 5-HT 2A receptor, whereas dissociatives and deliriants have been identified as noncompetitive NMDA receptor antagonists, and competitive muscarinic receptor antagonists, respectively. Salvinorin A is a potent κ-opioid receptor agonist. 7−12 Although all of these hallucinogenic drugs profoundly alter perception, according to the Hallucinogen Rating Scale (HRS) and the Five-Dimensional Altered States of Consciousness (5D-ASC) rating scale, there are also features that are unique to each of these groups. 13−15 Research using behavioral and cognitive tasks indicates that different groups of hallucinogens induce overlapping, yet distinct sets of changes in sensory processing. Recent findings regarding the molecular mechanism of action of psychedelic and other hallucinogenic drugs have been reviewed elsewhere. 7,8,11,16−24 In this review, we will discuss the effects of psychedelics in a range of animal behavioral assays, and their utility as preclinical models of the effects of these drugs in humans. ■ MODELING PSYCHOSIS IN ANIMALSModeling in rodents the neuropsychological effects induced by psychedelic drugs remains controversial. The above-mentioned psychometric rating scales HRS and 5D-ASC measure aspects of subjective experience such as "oceanic boundlessness", "dread of ego dissolution", and "spiritual expe...

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