A novel anxiogenic role for the delta opioid receptor expressed in GABaergic forebrain neurons

Paul Chu Sin Chung, Helen L. Keyworth, Elena Martin-Garcia, Pauline Charbogne, Emmanuel Darcq, Alexis Bailey, Dominique Filliol, Audrey Matifas, Grégory Scherrer, Abdel Mouttalib Ouagazzal, Claire Gaveriaux-Ruff, Katia Befort, Rafael Maldonado, Ian Kitchen, Brigitte L. Kieffer*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

Abstract

BACKGROUND: The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. METHODS: We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1fl/fl (Dlx-DOR) mice and tested main central DOR functions through behavioral testing. RESULTS: The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice. CONCLUSIONS: We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders.

Original languageEnglish
Pages (from-to)404-415
Number of pages12
JournalBiological Psychiatry
Volume77
Issue number4
DOIs
Publication statusPublished - 2015

Keywords

  • Conditional gene knockout
  • Delta opioid receptor
  • Emotion
  • Gabaergic forebrain neurons
  • Locomotion
  • Motivation

Fingerprint

Dive into the research topics of 'A novel anxiogenic role for the delta opioid receptor expressed in GABaergic forebrain neurons'. Together they form a unique fingerprint.

Cite this