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

by | Functional & Integrative Medicine

https://www.frontiersin.org/articles/10.3389/fncel.2017.00208/full

Comment; Great that we now appear to have another option to treat refractory depression.

Andrea Locci1, 

Philippe Geoffroy2, 

Michel Miesch2, 

Ayikoe-Guy Mensah-Nyagan3 and Graziano Pinna1*

  • 1The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
  • 2Laboratoire de Chimie Organique Synthétique, UMR 7177, Institut de Chimie de l’Université de Strasbourg, Strasbourg, France
  • 3Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France

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 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.

Introduction

Exposure to traumatic experiences is associated with a drastic increase in the risk of developing psychiatric disorders, including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). These debilitating conditions affect 8–16% of the adult population in the United States and MDD alone is the most common neuropsychiatric disease worldwide (Kessler et al., 2005; Berton and Nestler, 2006; Whiteford et al., 2013).

Severe traumas, including abuse in women, child abuse and neglect, combat situations or sexual assault, result in a particularly serious form of chronic PTSD that is often comorbid with MDD and suicide (Prigerson et al., 2001), and is associated with a marked increase in vulnerability to substance and alcohol abuse as well as mood disorders such as bipolar disorder, generalized anxiety, and phobias (Famularo et al., 1992; Agid et al., 1999; Heim and Nemeroff, 2001; Kendler et al., 2004). Furthermore, a history of early-life trauma can predict a more severe and chronic depression and inadequate response to both pharmacological and psychotherapeutic treatments and even failure of treatment response in adulthood (Kessler, 1997; Zlotnick et al., 1997; Lanquillon et al., 2000; Wiersma et al., 2009; Shamseddeen et al., 2011; Nanni et al., 2012). For example, multiple childhood adverse experiences increased fourfold the risk of developing MDD during adult life (Felitti et al., 1998), and increased 2–5 times the risk of attempted suicide in childhood, adolescence, and adulthood (Dube et al., 2001). A study in women demonstrated a tight correlation between sexual or physical abuse in childhood and increased symptoms of anxiety, MDD, addiction and suicide in adulthood (McCauley et al., 1997). Of note, abuse in general but most notably, abuse occurring between 4 and 7 years of age predicted a lower response to 8 weeks of selective serotonin reuptake inhibitors (SSRIs) (Williams et al., 2016). SSRIs remain the most used antidepressants for decades, however, only 40–50% of MDD patients achieve remission, and more than 1/3 develop pharmacoresistance (Golden et al., 2002; Rush et al., 2006; Kemp et al., 2008). Likewise, for PTSD treatment, the only drugs approved by the FDA are the SSRIs sertraline and paroxetine but only 20% of SSRI-treated PTSD patients do not relapse (Westenberg, 1996; Walderhaug et al., 2010; Ipser and Stein, 2012). The reasons underlying SSRI-resistance can be multiple and can be found in genetic factors, pharmacokinetics, type of trauma, and comorbidity with other mental disorders (El-Hage et al., 2013; Willner et al., 2013). Failure to achieve full remission from MDD and PTSD symptoms in a large portion of patients indicates the need to develop alternative drugs for the treatment of non-responders.

Both MDD and PTSD are associated with altered GABAergic neurotransmission. For example, adolescent as well as adult MDD patients show a reduction of plasma, CSF, and cerebral cortex GABA concentrations (Luscher et al., 2011). Moreover, the expression of several GABAA receptor subunits is altered in brain areas of MDD patients (Merali et al., 2004; Choudary et al., 2005; Klempan et al., 2009; Sequeira et al., 2009; Fatemi et al., 2013). Male Dutch veterans affected by PTSD show a significant reduction of benzodiazepine binding in cortex, hippocampus, and hypothalamus (Geuze et al., 2008), while male Viet Nam veterans show reduced binding in prefrontal cortex, Broadmann area 9 (Bremner et al., 2000). Furthermore, MDD and PTSD patients show low plasma, CSF, and brain levels of the GABAAreceptor-active, neurosteroid allopregnanolone (Allo) (Romeo et al., 1998; van Broekhoven and Verkes, 2003; Uzunova et al., 2006; Agis-Balboa et al., 2014). Depression during pregnancy and post-partum is likewise associated with changes in Allo levels (Nemeroff, 2008). Importantly, treatment with SSRIs normalizes CSF, plasma, and brain Allo levels in MDD patients, an effect associated with improved symptoms, while patients who fail to respond to SSRIs also fail to increase Allo levels (Romeo et al., 1998; Uzunova et al., 2006). Mouse stress models are probably the best translational approach to reproduce some of the behavioral and neurochemical alterations observed in MDD and PTSD patients. For example, the socially isolated (SI) mouse, a putative rodent model of PTSD, shows a time-dependent downregulation of corticolimbic Allo levels associated with behavioral dysfunction, such as aggressive behavior, anxiety-like behavior and altered contextual fear responses (Dong et al., 2001; Pinna et al., 2003; Pibiri et al., 2008; Nin et al., 2011a; Locci and Pinna, 2017a; Rasmusson et al., 2017). Furthermore, SI mice show changes in the expression of several GABAA receptor subunits, which similar to PTSD patients, result in resistance to benzodiazepine’s pharmacological effects (Pinna et al., 2006b; Geuze et al., 2008; Pibiri et al., 2008; Nin et al., 2011b). Intriguingly, administration of low doses of SSRIs, acting as selective brain steroidogenic stimulants (SBSSs), normalize brain Allo levels and improve behavior in SI mice (Pinna et al., 2003, 2009). Likewise, administration of the Allo analog, ganaxolone (GNX), results in a dose-dependent improvement of emotional behavior (Pinna and Rasmusson, 2014).

In this paper, we hypothesize that early (PND 21) adolescence social isolation contributes to a more rapid and severe development of aggression and a lower pharmacological response to S-fluoxetine (S-FLX) than mice isolated in late adolescence (PND 45), which will be demonstrated by (i) a lower reduction in the rate of aggression, (ii) a lower duration of the drugs effect, and (iii) a higher percent of “non responders.” We also compare the pharmacological effect of S-FLX with that of neurosteroid-based treatments, including the endocannabinoid, N-palmitoylethanolamine (PEA) that stimulates brain Allo biosynthesis or the Allo analogs, GNX, BR351, and BR297 that directly act at GABAA receptors.

The current study demonstrates that a single dose treatment with S-FLX, GNX, BR351, BR297, and PEA induced a stronger reduction of aggressive behavior in late than in early adolescent SI mice. Moreover, the rate of non-responders for all these drugs was higher in early SI mice and the pharmacological effect of these drugs was more enduring in late than early adolescent SI mice. Our data show that early SI mice develop earlier and more severe aggression than late SI mice and drugs like GNX, BR351, BR297, and PEA are stronger agents in counteracting these behavioral deficits.

Conclusion

PTSD and depression are multifactorial disorders with different symptom clusters and involve neurochemical deficits that may vary among individuals. Current treatment relies on SSRIs, which are efficacious only in a portion of patients. Early life traumatic events are associated with poor response to SSRI treatment. To assess treatment suitability, it would be important to screen PTSD and depressed patients for neurosteroid level downregulation (e.g., Allo) as a biomarker for diagnostic assessment. This may be important to guide precision therapy and could be helpful for designing appropriate intervention with neurosteroid-based synthetic molecules, including analogs of Allo or drugs that stimulate its synthesis such as the cannabinoids.

Collectively, data reported in this paper offer preclinical evidence in support of treatment alternatives for SSRI non-responders. Future studies are necessary to further clarify the precise molecular mechanisms involved in their behavioral improvement.

Dr. Raymond Oenbrink
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