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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References
- Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States.Int J Methods Psychiatr Res. 2012; 21: 169-184
- Evaluation of outcomes with citalopram for depression using measurement-based care in STAR∗D: Implications for clinical practice.Am J Psychiatry. 2006; 163: 28-40
- Treatment resistant depression: A multi-scale, systems biology approach.Neurosci Biobehav Rev. 2018; 84: 272-288
- Targeting opioid dysregulation in depression for the development of novel therapeutics.Pharmacol Ther. 2019; 201: 51-76
- Effects of morphine, naloxone and their interaction in the learned-helplessness paradigm in rats.Psychopharmacology. 1996; 123: 71-78
- Active behaviours produced by antidepressants and opioids in the mouse tail suspension test.Int J Neuropsychopharmacol. 2013; 16: 151-162
- Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.J Pharmacol Exp Ther. 2003; 305: 323-330
- Anxiolytic- and antidepressant-like activities of H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), a novel selective delta opioid receptor agonist.Peptides. 2008; 29: 93-103
- Potential anxiolytic and antidepressant-like activities of SNC80, a selective delta-opioid agonist, in behavioral models in rodents.J Pharmacol Sci. 2004; 95: 374-380
- Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats.Brain Res. 2006; 1069: 172-181
- NIH 11082 produces anti-depressant-like activity in the mouse tail-suspension test through a delta-opioid receptor mechanism of action.Eur J Pharmacol. 2007; 566: 132-136
- Enkephalin knockout male mice are resistant to chronic mild stress.Genes Brain Behav. 2014; 13: 550-558
- The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist.Transl Psychiatry. 2014; 4: e411
- The behavioral effects of the antidepressant tianeptine require the mu-opioid receptor.Neuropsychopharmacology. 2017; 42: 2052-2063
- The cloned mu, delta and kappa receptors and their endogenous ligands: Evidence for two opioid peptide recognition cores.Brain Res. 1995; 700: 89-98
- Endogenous opioid systems: Current concepts and clinical correlations.Neurology. 2012; 79: 807-814
- AAV ablates neurogenesis in the adult murine hippocampus.eLife. 2021; 10e59291
- Leucine-enkephalin and methionine-enkephalin produce opposing effects on plasma corticosterone levels in ether-stressed mice.Br J Pharmacol. 1980; 70: 509-511
- Reduced nucleus accumbens enkephalins underlie vulnerability to social defeat stress.Neuropsychopharmacology. 2019; 44: 1876-1885
- Use of preproenkephalin knockout mice and selective inhibitors of enkephalinases to investigate the role of enkephalins in various behaviours.Psychopharmacol (Berl). 2008; 196: 327-335
- Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors.PLoS One. 2014; 9e85136
- Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression.Neuron. 2009; 62: 479-493
- Chronic corticosterone administration induces negative valence and impairs positive valence behaviors in mice.Transl Psychiatry. 2019; 9: 337
- Behavioral response to fluoxetine in both female and male mice is modulated by dentate gyrus granule cell activity.Neurobiol Stress. 2020; 13100257
- Modeling treatment-resistant depression.Neuropharmacology. 2011; 61: 408-413
- Gene expression and proliferation biomarkers for antidepressant treatment resistance.Transl Psychiatry. 2017; 7e1061
- 5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response.Nat Neurosci. 2015; 18: 1606-1616
- GenePattern 2.0.Nat Genet. 2006; 38: 500-501
- WGCNA: An R package for weighted correlation network analysis.BMC Bioinformatics. 2008; 9: 559
- Div-Seq: Single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons.Science. 2016; 353: 925-928
- A sparse, spatially biased subtype of mature granule cell dominates recruitment in hippocampal-associated behaviors.Cell Rep. 2020; 31107551
- Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine.Psychopharmacol (Berl). 2008; 200: 557-572
- Environmental enrichment increases transcriptional and epigenetic differentiation between mouse dorsal and ventral dentate gyrus.Nat Commun. 2018; 9: 298
- Semilunar granule cells: Glutamatergic neurons in the rat dentate gyrus with axon collaterals in the inner molecular layer.J Neurosci. 2007; 27: 13756-13761
- Semilunar granule cells maintain distinct dendritic morphology and inhibition through postnatal development and receive heightened inhibition in adolescence.bioRxiv. 2019; https://doi.org/10.1101/2019.12.17.880005
- Engram-specific transcriptome profiling of contextual memory consolidation.Nat Commun. 2019; 10: 2232
- The dentate gyrus: Fundamental neuroanatomical organization (dentate gyrus for dummies).Prog Brain Res. 2007; 163: 3-22
- Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism.Mol Psychiatry. 2019; 24: 1779-1786
- Attenuation of antidepressant effects of ketamine by opioid receptor antagonism.Am J Psychiatry. 2018; 175: 1205-1215
- Ketamine metabolite (2R,6R)-hydroxynorketamine interacts with μ and κ opioid receptors.ACS Chem Neurosci. 2021; 12: 1487-1497
- A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.Psychopharmacology (Berl). 2016; 233: 1119-1130
- Depression: A new animal model sensitive to antidepressant treatments.Nature. 1977; 266: 730-732
- The forced swimming test as a model for core and component behavioral effects of antidepressant drugs.Behav Pharmacol. 1997; 8: 523-532
- Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.Science. 2003; 301: 805-809
- Resting-state connectivity biomarkers define neurophysiological subtypes of depression [published correction appears in Nat Med 2017;23:264].Nat Med. 2017; 23: 28-38
- Functional and optogenetic approaches to discovering stable subtype-specific circuit mechanisms in depression.Biol Psychiatry Cogn Neurosci Neuroimaging. 2019; 4: 554-566
- Serotonin 1A and serotonin 4 receptors: Essential mediators of the neurogenic and behavioral actions of antidepressants.Neuroscientist. 2016; 22: 26-45
- Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress.Neurobiol Dis. 2008; 31: 278-285
- Distribution of delta opioid receptor-expressing neurons in the mouse hippocampus.Neuroscience. 2012; 221: 203-213
- Emergence of 5-HT5A signaling in parvalbumin neurons mediates delayed antidepressant action.Mol Psychiatry. 2020; 25: 1191-1201
- Representing information in cell assemblies: Persistent activity mediated by semilunar granule cells.Nat Neurosci. 2010; 13: 213-222
Article Info
Publication History
Published online: June 14, 2022
Accepted:
May 18,
2022
Received in revised form:
May 17,
2022
Received:
December 16,
2020
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Society of Biological Psychiatry.
