Role of the orexin (hypocretin) system in contextual fear conditioning in rats

Wang, Huiying; Li, Sa; Kirouac, Gilbert J.

doi:10.1016/j.bbr.2016.08.052

Cited by 19 publications

(9 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, in a cue induced fear conditioning paradigm, Sears et al (2013) reported that OX enhances fear acquisition via OX1Rs and not OX2Rs and through a locus coeruleus-amygdala pathway. This is consistent with a study showing that systemic administration of OX1R, but not OX2R antagonists also attenuate freezing following contextual fear conditioning (Wang et al, 2017), and another study demonstrating that following cue or contextual fear conditioning, systemic or intra-amygdala administration of an OX1R antagonist enhanced extinction, and intracebral infusions of OXA impaired extinction (Flores et al, 2014). Yet, in this study administration of an OX2R antagonist did enhance contextual fear extinction while the orexin-B administration had no effect.…”

Section: Discussionsupporting

confidence: 90%

Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

et al. 2017

View full text Add to dashboard Cite

Orexin neurons originating in the perifornical and lateral hypothalamic area are highly reactive to anxiogenic stimuli and have strong projections to anxiety and panic-associated circuitry. Recent studies support a role for the orexin system and in particular the orexin 1 receptor (OX1R) in coordinating an integrative stress response. However, no selective OX1R antagonist has been systematically tested in two preclinical models of using panicogenic stimuli that induce panic attack in the majority of people with panic disorder, namely an acute hypercapnia-panic provocation model and a model involving chronic inhibition of GABA synthesis in the perifornical hypothalamic area followed by intravenous sodium lactate infusion. Here we report on a novel brain penetrant, selective and high affinity OX1R antagonist JNJ-54717793 (1S,2R,4R)-7-([(3-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-N-[5-(trifluoromethyl)pyrazin-2-yl]-7-azabicyclo[2.2.1]heptan-2-amine). JNJ-54717793 is a high affinity/potent OX1R antagonist and has an excellent selectivity profile including 50 fold versus the OX2R. Ex vivo receptor binding studies demonstrated that after oral administration JNJ-54717793 crossed the blood brain barrier and occupied OX1Rs in the rat brain. While JNJ-54717793 had minimal effect on spontaneous sleep in rats and in wild-type mice, its administration in OX2R knockout mice, selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. JNJ-54717793 attenuated CO2 and sodium lactate induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. These data confirm that selective OX1R antagonism may represent a novel approach of treating anxiety disorders, with no apparent sedative effects.

show abstract

Section: Discussionsupporting

confidence: 90%

Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In contrast, mice lacking OX 2 R show reduced freezing in a contextual but not cued fear paradigms (Soya et al, 2013). However, a more recent study using specific orexin antagonists has found that the OX 1 R, and not the OX 2 R is important in regulating contextual fear (Wang et al, 2017). While much of contextual and cued fear is attributed to the hippocampus and amygdala (Johnson et al, 2012), which express both orexin receptors (Marcus et al, 2001), the PVT (which receives dense orexinergic projections) has also been found to be important regulating the fear response; lesioning the PVT decreases freezing in response to cued fear conditioning (Li et al, 2014).…”

Section: Orexins and Phenotypes Relevant To Mental Healthmentioning

confidence: 99%

Orexins and stress

Grafe

Bhatnagar

2018

Frontiers in Neuroendocrinology

View full text Add to dashboard Cite

The neuropeptides orexins are important in regulating the neurobiological systems that respond to stressful stimuli. Furthermore, orexins are known to play a role many of the phenotypes associated with stress-related mental illness such as changes in cognition, sleep-wake states, and appetite. Interestingly, orexins are altered in stress-related psychiatric disorders such as Major Depressive Disorder and Anxiety Disorders. Thus, orexins may be a potential target for treatment of these disorders. In this review, we will focus on what is known about the role of orexins in acute and repeated stress, in stress-induced phenotypes relevant to psychiatric illness in preclinical models, and in stress-related psychiatric illness in humans. We will also briefly discuss how orexins may contribute to sex differences in the stress response and subsequent phenotypes relevant to mental health, as many stress-related psychiatric disorders are twice as prevalent in women.

show abstract

“…Clinical research showed a reduced amygdala activity during aversive conditioning in human narcolepsy ( Ponz et al, 2010 ), a pathophysiological condition associated with a loss of orexin neurons ( Peyron et al, 2000 ). Pharmacological blockade or genetic deletion of OX1R impaired contextual and cued fear conditioning ( Sears et al, 2013 ; Soya et al, 2013 ; Flores et al, 2014 ; Wang et al, 2017 ) in rodents. Moreover, OX1R antagonism facilitated the consolidation of both contextual and cued fear extinction ( Flores et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations

Flores

Herry

Maldonado

et al. 2017

International Journal of Neuropsychopharmacology

View full text Add to dashboard Cite

BackgroundOrexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated.MethodsWe used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation.ResultsTreatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala.ConclusionsThese data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867.

show abstract

Role of the orexin (hypocretin) system in contextual fear conditioning in rats

Cited by 19 publications

References 32 publications

Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

Orexins and stress

Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations

Contact Info

Product

Resources

About