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Cited by 52Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Social Isolation in Early versus Late Adolescent Mice Is Associated with Persistent Behavioral Deficits That Can Be Improved by Neurosteroid-Based Treatment

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Locci, Andrea, Geoffroy, Philippe, Miesch, Michel, Mensah-Nyagan, Ayikoe-Guy, Pinna, Graziano·2017·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2017.00208PMC PMC5581875
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Abstract

Early trauma and stress exposure during a critical period of life may increase the risk of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) in adulthood. The first-choice treatment for MDD and PTSD are selective serotonin reuptake inhibitor (SSRI) antidepressants. Unfortunately, half of MDD and PTSD patients show resistance to the therapeutic effects of these drugs and more efficient treatments are essential. Both MDD and PTSD patients present reduced levels of allopregnanolone (Allo), a potent endogenous positive allosteric modulator of GABA action at GABAA receptors (GABAARs), which are normalized by SSRIs in treatment responders. Thus, Allo analogs or drugs that stimulate its levels may offer an alternative in treating SSRIs-non-responders. We tested several drugs on the aggressive behavior of early and late adolescent socially-isolated (SI) mice, a model of PTSD. Isolation in early adolescence (PND 21) induced more severe aggression than mice isolated at PND 45. A single non-sedating administration of S-fluoxetine (S-FLX; 0.375-1.5 mg/kg), or of the Allo analogs ganaxolone (GNX; 10 mg/kg), BR351 (1-5 mg/kg), or BR297 (0.3125-2.5 mg/kg), or of the endocannabinoid, N-palmitoylethanolamine (PEA; 5-20 mg/kg) all decreased aggression more effectively in late than early adolescent SI mice. Importantly, the number of drug non-responders was higher in early than late SI mice for all the drugs tested. The non-responder rate was more elevated (12-64%) after S-FLX treatment, while 100% of mice responded to a single administration of PEA at the dose range of 15-20 mg/kg. Moreover, GNX, BR351 and BR297's antiaggressive effect persisted longer than S-FLX in both late and early SI mice. All drugs tested failed to alter locomotor activity of SI mice. Our results show that drugs that mimic Allo’s action or that induce Allo biosynthesis may be valuable for the treatment of "SSRIs non-responder" patients.

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Cited by

Sorted by citations

Authors
Locci, A., Geoffroy, P., Miesch, M., Mensah-Nyagan, A.-G., & Pinna, G.
Affiliations
  • University of Illinois Chicago (US)
  • Institut de Chimie de Strasbourg (FR)
Corresponding author
Pinna, Graziano
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2017-08-29
Volume
11
Pages
208-208
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2017.00208
PMC
PMC5581875
OpenAlex
W2751372623
Cited by
52
References
10
Citations by year
2026: 2 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 12 · 2021: 9 · 2020: 2 · 2019: 6 · 2018: 6
FWCI
2.67
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Defense (W81XWH-15-1-0521)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
social isolation, adolescent mice, allopregnanolone, neurosteroids, aggression, post-traumatic stress disorder, major depressive disorder, fluoxetine, ganaxolone, N-palmitoylethanolamine, endocannabinoids, GABAA receptor, behavioral deficits

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