Cortical 5-HT
            <sub>2A</sub>
            Receptor Signaling Modulates Anxiety-Like Behaviors in Mice

Weisstaub, Noelia V.; Zhou, Ming‐Ming; Lira, Alena; Lambe, Evelyn K.; González-Maeso, Javier; Hornung, Jean‐Pierre; Sibille, Etienna; Underwood, Mark D.; Itohara, Shigeyoshi; Dauer, William T.; Ansorge, Mark S.; Morelli, Emanuela; Mann, J. John; Tóth, Miklós; Aghajanian, George K.; Sealfon, Stuart C.; Hen, René; Gingrich, Jay A.

doi:10.1126/science.1123432

Cited by 381 publications

(285 citation statements)

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“…The pharmacological data are extended by the finding that gene knockout of the mouse Htr2a causes a decrease in anxiety-like behavior in various tasks (Weisstaub et al, 2006). Weisstaub et al were able to demonstrate that expressing 5-HT2A-Rs in the cortex of these knockout mice was sufficient to normalize the anxiety-like behavior, suggesting that cortical 5-HT2A-Rs normally serve to promote anxiety-like behavior.…”

Section: -Ht2a Receptorsmentioning

confidence: 98%

“…Precisely how this relates to the regulation of mPFC neuronal activity by 5-HT2A-Rs is not yet clear. Furthermore, although 5-HT2A-R knockout mice showed normal 'depression-related' behavior in the forced swim test, and a normal HPA-axis response to this stressor (Weisstaub et al, 2006) further examination of these mice for other stress-related behaviors would be informative. Such studies are encouraged by the increased PFC 5-HT2A-R binding found in depression (Meyer et al, 1999;Yatham et al, 2000), and the antidepressant efficacy of drugs with 5-HT2A-R antagonist properties (e.g., nefazodone, trazodone, mirtazapine) Millan, 2003).…”

Section: -Ht2a Receptorsmentioning

confidence: 99%

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Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

243

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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Section: -Ht2a Receptorsmentioning

confidence: 98%

Section: -Ht2a Receptorsmentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

243

166

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“…99 These mice show decreased anxiety-like behavior, and rescuing 5-HT 2A receptor expression in cortical neurons normalizes anxiety-like behavior. 99 It has also been suggested that stimulation of 5-HT 2A receptors in the dorsal periaqueductal gray matter induces panicolytic-like behavior in rats.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

Animal Models of Serotonergic Psychedelics

Hanks

González-Maeso

2012

ACS Chem. Neurosci.

131

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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“…The knockout mice exhibited greater exploratory and risk behavior in conflict paradigms, such as the open field, dark-light choice, elevated plus-maze, and novelty-suppressed feeding tests. In depression-related behaviors, as measured by the forced swim test and the tail suspension test, the mice did not differ significantly from wild-type mice (54).…”

Section: Fig 3 Group Mean Ventilatory Response To Itto For Experimementioning

confidence: 71%

“…Activation of HTR2A receptors weakens the sensory gating so that more sensory information is able to reach consciousness, which in turn can lead to the pathology of anxiety disorders (29). Behavioral studies in HTR2A knockout mice have shown changes in anxiety-related but not depression-related paradigms (54). The knockout mice exhibited greater exploratory and risk behavior in conflict paradigms, such as the open field, dark-light choice, elevated plus-maze, and novelty-suppressed feeding tests.…”

Section: Fig 3 Group Mean Ventilatory Response To Itto For Experimementioning

confidence: 99%

Tracheal occlusion modulates the gene expression profile of the medial thalamus in anesthetized rats

Bernhardt¹,

García-Reyero

Vovk³

et al. 2011

Journal of Applied Physiology

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scious awareness of breathing requires the activation of higher brain centers and is believed to be a neural gated process. The thalamus could be responsible for the gating of respiratory sensory information to the cortex. It was reasoned that if the thalamus is the neural gate, then tracheal obstructions will modulate the gene expression profile of the thalamus. Anesthetized rats were instrumented with an inflatable cuff sutured around the trachea. The cuff was inflated to obstruct 2-4 breaths, then deflated for a minimum of 15 breaths. Obstructions were repeated for 10 min followed by immediate dissection of the medial thalamus. Following the occlusion protocol, 588 genes were found to be altered (P Ͻ 0.05; log2 fold change Ն 0.4), with 327 genes downregulated and 261 genes upregulated. A significant upregulation of the serotonin HTR2A receptor and significant downregulation of the dopamine DRD1 receptor genes were found. A pathway analysis was performed that targeted serotonin and dopamine receptor pathways. The mitogen-activated protein kinase 1 (MAPK1) gene was significantly downregulated. MAPK1 is an inhibitory regulator of HTR2A and facilitatory regulator for DRD1. Downregulation of MAPK1 may be related to the significant upregulation of HTR2A and downregulation of DRD1, suggesting an interaction in the medial thalamus serotonin-dopamine pathway elicited by airway obstruction. These results demonstrate an immediate change in gene expression in thalamic arousal, fear, anxiety motivation-related serotonin and dopamine receptors in response to airway obstruction. The results support the hypothesis that the thalamus is a component in the respiratory mechanosensory neural pathway. respiratory loading; microarray; stress; serotonin; dopamine THE RESPIRATORY SYSTEM is continually active, and any prolonged interruption is a threat to an animal's survival. Thus it is of critical importance to maintain ventilation in the face of a variety of stimuli by adjusting the breathing pattern. Clark and von Euler (13) described the relationship between lung volume and breath timing in anesthetized cats. They demonstrated that inspiratory time (TI) depends on inspiratory volume and that the subsequent expiratory time (TE) depends on the preceding TI. A similar volume-timing relationship was found when a mechanical stimulus in the form of an external resistive load was applied. Loading of the inspiratory (57) or expiratory (33) phase caused a decrease in volume and an increase in the duration of the respective loaded breath phase. The response to the added loads was called the respiratory load compensation reflex. Load compensation is a sensory motor response.A sufficiently high load on the respiratory system results in the sensation of dyspnea, or breathlessness, which is one of the primary symptoms in pulmonary and cardiovascular diseases (40, 44). It is one of the main symptoms that limits patients with obstructive pulmonary diseases, and it can also be considered one of the most important factors in determining the severi...

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Cortical 5-HT _2A Receptor Signaling Modulates Anxiety-Like Behaviors in Mice

Cited by 381 publications

References 28 publications

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Animal Models of Serotonergic Psychedelics

Tracheal occlusion modulates the gene expression profile of the medial thalamus in anesthetized rats

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Cortical 5-HT 2A Receptor Signaling Modulates Anxiety-Like Behaviors in Mice

Cited by 381 publications

References 28 publications

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Animal Models of Serotonergic Psychedelics

Tracheal occlusion modulates the gene expression profile of the medial thalamus in anesthetized rats

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Cortical 5-HT _2A Receptor Signaling Modulates Anxiety-Like Behaviors in Mice