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 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.
Highlights
Severe traumas, including abuse in women, child abuse and neglect, combat situations or sexual assault, result in a serious form of chronic post-traumatic stress disorder (PTSD) that is often comorbid with major depressive disorder (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)
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
We found that early isolation, which was started at PND 21, induced a more rapid and severe development of aggression compared to late social isolation, which was started at PND 45
Summary
Severe traumas, including abuse in women, child abuse and neglect, combat situations or sexual assault, result in a 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). 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
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