title: Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network.
abstract: BACKGROUND
  Although the hypothalamic orexin system is known to regulate appetitive behaviors and promote wakefulness and arousal (Sakurai, 2007 [56]), this system may also be important in adaptive and pathological anxiety/stress responses (Suzuki et al., 2005 [4]). In a recent study, we demonstrated that CSF orexin levels were significantly higher in patients experiencing panic attacks compared to non-panicking depressed subjects (Johnson et al., 2010 [9]). Furthermore, genetically silencing orexin synthesis or blocking orexin 1 receptors attenuated lactate-induced panic in an animal model of panic disorder. Therefore, in the present study, we tested if orexin (ORX) modulates panic responses and brain pathways activated by two different panicogenic drugs.
  
  
  METHODS
  We conducted a series of pharmacological, behavioral, physiological and immunohistochemical experiments to study the modulation by the orexinergic inputs of anxiety behaviors, autonomic responses, and activation of brain pathways elicited by systemic injections of anxiogenic/panicogenic drugs in rats.
  
  
  RESULTS
  We show that systemic injections of two different anxiogenic/panicogenic drugs (FG-7142, an inverse agonist at the benzodiazepine site of the GABA(A) receptor, and caffeine, a nonselective competitive adenosine receptor antagonist) increased c-Fos induction in a specific subset of orexin neurons located in the dorsomedial/perifornical (DMH/PeF) but not the lateral hypothalamus. Pretreating rats with an orexin 1 receptor antagonist attenuated the FG-7142-induced anxiety-like behaviors, increased heart rate, and neuronal activation in key panic pathways, including subregions of the central nucleus of the amygdala, bed nucleus of the stria terminalis, periaqueductal gray and in the rostroventrolateral medulla.
  
  
  CONCLUSIONS
  Overall, the data here suggest that the ORX neurons in the DMH/PeF region are critical to eliciting coordinated panic responses and that ORX1 receptor antagonists constitute a potential novel treatment strategy for panic and related anxiety disorders. The neural pathways through which ORX1 receptor antagonists attenuate panic responses involve the extended amygdala, periaqueductal gray, and medullary autonomic centers.
authors.affiliation: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA. philjohn@iupui.edu
authors.forename: Philip L
authors.initials: PL
authors.lastname: Johnson
authors.forename: Brian C
authors.initials: BC
authors.lastname: Samuels
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Fitz
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Federici
authors.forename: Nathan
authors.initials: N
authors.lastname: Hammes
authors.forename: Maureen C
authors.initials: MC
authors.lastname: Early
authors.forename: William
authors.initials: W
authors.lastname: Truitt
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lowry
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002110:Caffeine / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology; D064446:Orexin Receptors; D010200:Panic / Q000187:drug effects* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000187:drug effects* / Q000502:physiology; D012686:Septal Nuclei / Q000187:drug effects / Q000502:physiology
chemical_list: D002243:Carbolines; D000697:Central Nervous System Stimulants; D018756:GABA Antagonists; D064446:Orexin Receptors; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D002110:Caffeine; C035874:FG 7142