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Orexin neuropeptides contribute to the development and persistence of generalized avoidance behavior in the rat

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Abstract

Rationale

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.

Conclusion

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.

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Acknowledgments

We thank Rebekka Pietrek, Cedric Fischer, and Malvina Louis (all Actelion Pharmaceuticals) for their excellent technical assistance, Carla Sciarretta (Actelion) for valuable suggestions on the manuscript, and Catherine Brisbare-Roch (Actelion) and Jed Black (Stanford) for conceptual contributions.

Conflict of interest

All authors were employees of Actelion Pharmaceuticals Ltd. at the time the study was conducted. They have no other financial conflicts of interest to declare.

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Author notes

  1. Daniele Viviani

    Present address: Novartis Pharma Schweiz AG, Monbijoustrasse 118, 3007, Bern, Switzerland

  2. Patrizia Haegler

    Present address: Clinical Pharmacology Group, Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031, Basel, Switzerland

Authors and Affiliations

  1. Department of CNS-Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Daniele Viviani, Patrizia Haegler, Francois Jenck & Michel A. Steiner

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  1. Daniele Viviani
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  2. Patrizia Haegler
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Correspondence to Michel A. Steiner.

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Viviani, D., Haegler, P., Jenck, F. et al. Orexin neuropeptides contribute to the development and persistence of generalized avoidance behavior in the rat. Psychopharmacology 232, 1383–1393 (2015). https://doi.org/10.1007/s00213-014-3769-x

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  • DOI: https://doi.org/10.1007/s00213-014-3769-x

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