Abstract
Background
Selective serotonin reuptake inhibitors such as fluoxetine have a limited treatment
efficacy. The mechanism by which some patients respond to fluoxetine while others
do not remains poorly understood, limiting treatment effectiveness. We have found
the opioid system to be involved in the responsiveness to fluoxetine treatment in
a mouse model for anxiety- and depressive-like behavior.
Methods
We analyzed gene expression changes in the dentate gyrus of mice chronically treated
with corticosterone and fluoxetine. After identifying a subset of genes of interest,
we studied their expression patterns in relation to treatment responsiveness. We further
characterized their expression through in situ hybridization and the analysis of a
single-cell RNA sequencing dataset. Finally, we behaviorally tested mu and delta opioid
receptor knockout mice in the novelty suppressed feeding test and the forced swim
test after chronic corticosterone and fluoxetine treatment.
Results
Chronic fluoxetine treatment upregulates proenkephalin expression in the dentate gyrus,
and this upregulation is associated with treatment responsiveness. The expression
of several of the most significantly upregulated genes, including proenkephalin, is
localized to an anatomically and transcriptionally specialized subgroup of mature
granule cells in the dentate gyrus. We have also found that the delta opioid receptor
contributes to some, but not all, of the behavioral effects of fluoxetine.
Conclusions
These data indicate that the opioid system is involved in the antidepressant effects
of fluoxetine, and this effect may be mediated through the upregulation of proenkephalin
in a subpopulation of mature granule cells.
Keywords
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Article Info
Publication History
Published online: June 14, 2022
Accepted:
May 18,
2022
Received in revised form:
May 17,
2022
Received:
December 16,
2020
Identification
Copyright
© 2022 Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Opioid Systems and Depression: The Relationship Is StrengtheningBiological PsychiatryVol. 92Issue 12
- PreviewPrior to the mid-20th century, the acute euphoric effects of opioid drugs and their ability to alleviate depression were primary reasons for physician prescriptions of opioid drugs. This practice was abandoned and discouraged once it was recognized that tolerance, withdrawal, and dependence lead to iatrogenic addiction and opioid use disorder. Nevertheless, the field has far from discarded the connection of the opioid systems with depression [recently reviewed by Jelen et al. (1)], including evidence that nonmedical opioid use may precipitate new-onset depressive episodes (2).
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