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Administration of a delta opioid receptor agonist KNT-127 to the basolateral amygdala has robust anxiolytic-like effects in rats

Abstract

Rationale

We previously reported that systemic administration of a selective delta opioid receptor (DOP) agonist, KNT-127, produced potent anxiolytic-like effects in rats. Interestingly, DOPs are highly distributed in the basolateral region of the amygdala (BLA).

Objectives

In this study, we investigated the effect of intra-BLA administration of KNT-127 on anxiety-like behaviors in rats.

Methods and Results

In the elevated plus maze test, bilateral injection of KNT-127 into the BLA significantly and dose-dependently increased time spent in the open arms. The magnitude of KNT-127 (0.08 μg/0.2 μl)-induced anxiolytic-like effects was similar to muscimol (0.1 μg/0.2 μl), which is a selective agonist for the gamma amino butyric acid type A receptors. Further, anxiolytic-like effects of KNT-127 were abolished by pretreatment with naltrindole, a selective DOP antagonist, suggesting that KNT-127-induced anxiolytic-like effects are mediated by DOPs. These anxiolytic-like effects were confirmed using another innate anxiety model, the open field test. Interestingly, intra-BLA administration of KNT-127 also induced anxiolytic-like effects in the contextual fear conditioning test. Moreover, these effects were also abolished by naltrindole pretreatment. Finally, we demonstrated that intra-BLA administration of KNT-127 facilitates extinction learning of contextual fear in conditioned rats.

Conclusions

Altogether, our findings clearly demonstrate that intra-BLA administration of KNT-127 in rats has robust anxiolytic-like effects not only in innate anxiety-like behavioral tests but also in the contextual fear conditioning test.

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Acknowledgments

We thank Rachel James, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This research was financially supported by an Intramural Research Grant (24-2, 27-1, 30-1) for Neurological and Psychiatric Disorders provided by the National Center of Neurology and Psychiatry, Japan (NCNP). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Correspondence to Mitsuhiko Yamada.

Ethics declarations

The studies were conducted in accordance with protocols approved by the Institutional Animal Care and Use Committee of the Japanese National Center of Neurology and Psychiatry (Approval No. 2010001).

Conflict of interests

The authors declare that they have no conflict of interest.

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Sugiyama, A., Yamada, M., Saitoh, A. et al. Administration of a delta opioid receptor agonist KNT-127 to the basolateral amygdala has robust anxiolytic-like effects in rats. Psychopharmacology 235, 2947–2955 (2018). https://doi.org/10.1007/s00213-018-4984-7

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  • DOI: https://doi.org/10.1007/s00213-018-4984-7

Keywords

  • Anxiety
  • Contextual fear conditioning
  • KNT-127
  • D-cycloserine
  • Basolateral amygdala