title: Orexin neuropeptides contribute to the development and persistence of generalized avoidance behavior in the rat.
abstract: BACKGROUND
  Avoidance of contexts directly associated with fearful experiences represents an adaptive behavioral survival strategy. Over-interpretation of contextual cues leading to generalized avoidance of situations that are only remotely similar to the original fear context represents a pathologic process that contributes to anxiety disorders. Orexin neuropeptides modulate anxiety-like behavioral and physiological responses.
  
  
  OBJECTIVE
  The objective of this paper was to investigate the impact of pharmacological orexin receptor blockade on generalized avoidance behavior.
  
  
  METHODS
  Rats received a single electric foot-shock in the dark side of a two-compartment shuttle box followed by situational context reminders. After shock, rats were treated chronically (3 weeks) with the orexin receptor antagonist almorexant or with the selective serotonin reuptake inhibitor sertraline, used as positive anxiolytic control. In week 3, avoidance behavior was measured under conditions of high (dark-light (DL)-box) and low (elevated plus maze (EPM)) similarity to the original shock context. Avoidance behavior was re-assessed 5 and 17 weeks after treatment termination.
  
  
  RESULTS
  Avoidance in the DL box (contextual fear memory) remained unaffected by any treatment and lasted 20 weeks post-shock exposure. Avoidance in the EPM (neophobic fear generalization) was partially attenuated during treatment with almorexant and sertraline at week 3. Following 5 and 17 weeks of drug washout, avoidance in the EPM was significantly reduced in almorexant- but not in sertraline-treated rats. Almorexant also reduced persistent avoidance in the EPM upon treatment initiation 3 weeks after shock exposure.
  
  
  CONCLUSIONS
  Chronic orexin receptor blockade in rats reduces both the development and persistence of generalized avoidance in situations with low similarity to the initial shock context.
authors.affiliation: Department of CNS-Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Daniele
authors.initials: D
authors.lastname: Viviani
authors.forename: Patrizia
authors.initials: P
authors.lastname: Haegler
authors.forename: Francois
authors.initials: F
authors.lastname: Jenck
authors.forename: Michel A
authors.initials: MA
authors.lastname: Steiner
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D004597:Electroshock / Q000009:adverse effects / Q000523:psychology*; D005239:Fear / Q000187:drug effects / Q000502:physiology* / Q000523:psychology*; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020280:Sertraline / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000081:Acetamides; D007546:Isoquinolines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; C519150:almorexant; D020280:Sertraline