Activation of α2 Adrenergic Receptors Suppresses Fear Conditioning: Expression of c-Fos and Phosphorylated CREB in Mouse Amygdala

Davies, M. Frances; Tsui, Janet Y.; Flannery, Judy A.; Li, Xiangqi; DeLorey, Timothy M.; Hoffman, Brian B.

doi:10.1038/sj.npp.1300324

Cited by 61 publications

(20 citation statements)

References 75 publications

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“…Dexmedetomidine is preferable for immunocompromised patients, because neither lymphocyte dysfunction nor attenuated lymphocyte proliferation was found at clinically relevant plasma concentrations 20. While dexmedetomidine showed age-dependent hypnotic sensitivity, as demonstrated by potent hypnosis in neonatal rats 22, it is subhypnotic to mice at a dose of 50 µg/kg 23. The dose used in this study was lower than 50 µg/kg and exerted an antinociceptive effect on formalin-induced pain.…”

Section: Discussionmentioning

confidence: 78%

The Antinociceptive Effect of Dexmedetomidine Modulates Spleen Cell Immunity in Mice

Jang

Yeom²,

Kang³

et al. 2014

Int. J. Med. Sci.

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Background: Pain plays roles in both the nervous system and immune system. Changes in the neuroendocrine pathway under pain conditions give rise to sympathetic outflow with increased plasma catecholamines and activate immune reactions. Dexmedetomidine exerts sedative, analgesic, and anesthetic-sparing effects and is known to diminish pro-inflammatory processes by central sympatholytic effects. To investigate the influence of the analgesic effect of dexmedetomidine on immunomodulation under pain conditions, splenic natural killer (NK) tumoricidal cytotoxic activity, proliferative ability of T lymphocytes, and cytokine changes were assessed.Methods: After evaluation of the analgesic efficacy of dexmedetomidine in C57BL mice that were subjected to formalin-induced pain, dexmedetomidine (30 µg/kg) or saline was injected intraperitoneally (ip) 30 min before formalin (20 µL of 2% formalin in 0.9% saline) injection. NK cell activity against NK-sensitive YAC-1 lymphoma cells was evaluated by the percentage of specific lactate dehydrogenase (LDH) release. Various numbers of effector cells (NK cells) were added to the wells of a microtiter plate containing 2 × 104 target YAC-1 cells in 100 μL, to achieve final effector-to-target cell ratios of 80:1, 40:1, and 20:1. The level of lymphocyte proliferation in response to phytohemagglutinin (PHA) was detected by bromodeoxyuridine (BrdU) incorporation assay. TNF-α, IL-1β, and IL-10 levels were determined in blood samples and supernatants of splenocyte preparations.Results: IP administration of dexmedetomidine significantly decreased the time of licking and biting during the first and second phases of the formalin test (p <0.001). Formalin-induced pain led to higher activity of NK cells than in sham-treated mice (p <0.05), but NK activity was not increased significantly by ip dexmedetomidine treatment. Formalin-induced pain significantly increased splenic lymphocyte proliferation (p <0.05), but dexmedetomidine did not alter this response. There was a significant increase in plasma TNF-α (p = 0.048) and IL-6 (p = 0.014) levels after formalin-induced pain. However, the differences between the responses after ip dexmedetomidine did not change significantly.Conclusions: Dexmedetomidine showed antinociceptive effect on both of acute pain phase 1 and hyperalgesic phase 2 of formalin pain model. Formalin-induced pain alters cellular immunity of spleen in mice. Dexmedetomidine attenuates the activation of NK cells under pain condition, but neither the proliferative response of the splenic lymphocytes nor the cytokine production was affected by dexmedetomidine.

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Section: Discussionmentioning

confidence: 78%

The Antinociceptive Effect of Dexmedetomidine Modulates Spleen Cell Immunity in Mice

Jang

Yeom²,

Kang³

et al. 2014

Int. J. Med. Sci.

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“…The α2 adrenoceptor agonist dexmedetomidine indeed blocks fear consolidation (Davies et al, 2004), although this was tested in normal mice not in a PTSD mouse model. However, no preventive clinical PTSD studies using α2 adrenoceptor agonists have been reported.…”

Section: Preventionmentioning

confidence: 99%

Pharmacological treatment of PTSD – Established and new approaches

2012

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A large proportion of humans will experience a traumatic event at least once in their lifetime, with up to 10% then going on to developing post-traumatic stress disorder (PTSD). In this review we will discuss established pharmacological interventions for PTSD as well as highlight novel therapeutic strategies undergoing extensive preclinical research as well as ongoing clinical research. Such strategies include prophylactic treatments and use of pharmacotherapy as adjunctive treatment with established trauma-focused psychological therapies. These potential treatment approaches include modulation of stress effects on memory consolidation after trauma (e.g. glucocorticoid, corticotropin releasing factor and norepinephrine signalling modulators), as well as putative cognitive enhancers that target mechanisms of conditioned fear extinction and reconsolidation (e.g. glucocorticoid receptor modulators and modulators of glutamate signalling such as positive allosteric modulators of glutamate receptors, glycine transporter inhibitors, glycine agonists, autoreceptor antagonists). We will discuss evidence for and against these potential novel treatment strategies and their limitations.

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“…Elevating cAMP levels leads to the activation of cAMP dependent kinases, such as MAPK, PKA and PKC, which in turn phosphorylates CREB. Phosphorylated CREB is a transcription factor that upregulates gene transcription, including immediate-early genes such as c-fos and Arc (Davies et al, 2004; Blundell and Adamec, 2007; Orman and Stewart, 2007; Canal et al, 2008). Expression of Arc protein is induced by strong synaptic activation and is quickly transported to the active dendrites to participate in synaptic remodeling during associative learning and LTP (Bramham et al, 2008; Miyashita et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Differential activation of amygdala Arc expression by positive and negatively valenced emotional learning conditions

Young

Williams

2013

Front. Behav. Neurosci.

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Norepinephrine is released in the amygdala following negatively arousing learning conditions. This event initiates a cascade of changes including the transcription of activity-regulated cytoskeleton-associated protein (Arc) expression, an early-immediate gene associated with memory encoding. Recent evidence suggests that the valence of emotionally laden encounters may generate lateralized, as opposed to symmetric release of this transmitter in the right or left amygdala. It is currently not clear if valence-induced patterns of selective norepinephrine output across hemispheres are also reproduced in downstream pathways of cellular signaling necessary for memory formation. This question was addressed by determining if Arc expression is differentially distributed across the right and left amygdala following exposure to positively or negatively valenced learning conditions respectively. Male Sprague Dawley rats were randomly assigned to groups exposed to the Homecage only, five auditory tones only, or five auditory tones paired with footshock (0.35 mA) during Pavlovian fear conditioning. Western blot analysis revealed that Arc expression in the right amygdala was elevated significantly above that observed in the left amygdala 60 and 90 min following fear conditioning. Similarly, subjects exposed to a negatively valenced outcome consisting of an unexpected reduction in food rewards showed a greater level of Arc expression in only the right, but not left basolateral amygdala. Presenting a positively valenced event involving an unexpected increase in food reward magnitude following bar pressing, resulted in significantly greater Arc expression in the left, but not right basolateral amygdala (p < 0.01). These findings indicate that the valence of emotionally arousing learning conditions is reflected at later stages of synaptic plasticity involving the transcription of immediate early genes such as Arc.

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Activation of α2 Adrenergic Receptors Suppresses Fear Conditioning: Expression of c-Fos and Phosphorylated CREB in Mouse Amygdala

Cited by 61 publications

References 75 publications

The Antinociceptive Effect of Dexmedetomidine Modulates Spleen Cell Immunity in Mice

The Antinociceptive Effect of Dexmedetomidine Modulates Spleen Cell Immunity in Mice

Pharmacological treatment of PTSD – Established and new approaches

Differential activation of amygdala Arc expression by positive and negatively valenced emotional learning conditions

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