Neurosteroids reduce social isolation-induced behavioral deficits: a proposed link with neurosteroid-mediated upregulation of BDNF expression

Abstract

The pharmacological action of selective serotonin reuptake inhibitor antidepressants may include a normalization of the decreased brain levels of the brain-derived neurotrophic factor (BDNF) and of neurosteroids such as the progesterone metabolite allopregnanolone, which are decreased in patients with depression and posttraumatic stress disorders (PTSD). The allopregnanolone and BDNF level decrease in PTSD and depressed patients is associated with behavioral symptom severity. Antidepressant treatment upregulates both allopregnanolone levels and the expression of BDNF in a manner that significantly correlates with improved symptomatology, which suggests that neurosteroid biosynthesis and BDNF expression may be interrelated. Preclinical studies using the socially isolated mouse as an animal model of behavioral deficits, which resemble some of the symptoms observed in PTSD patients, have shown that fluoxetine and derivatives improve anxiety-like behavior, fear responses and aggressive behavior by elevating the corticolimbic levels of allopregnanolone and BDNF mRNA expression. These actions appeared to be independent and more selective than the action of these drugs on serotonin reuptake inhibition. Hence, this review addresses the hypothesis that in PTSD or depressed patients, brain allopregnanolone levels, and BDNF expression upregulation may be mechanisms at least partially involved in the beneficial actions of antidepressants or other selective brain steroidogenic stimulant molecules.

Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder

“…Therefore, we studied the level of Allo in post-TDS rats after the administration of YL-IPA08 to substantiate this hypothesis. Our results showed decreased Allo levels in the prefrontal cortex and serum in post-TDS rats, which is consistent with preclinical studies (Pinna et al, 2003(Pinna et al, , 2006aNin et al, 2011). We also found that the lowered Allo levels were reversed by YL-IPA08 treatment in post-TDS rats, and that these effects were antagonized by PK11195, further suggesting that the anti-PTSD effects of YL-IPA08 were mediated by binding to TSPO and the subsequent synthesis of Allo.…”

“…Interestingly, the socially isolated mouse fails to respond to the anxiolytic action of BZDs (diazepam and zolpidem) that fail to modulate GABAA receptors containing α4 and α6 subunits (Pinna et al, 2000(Pinna et al, , 2006bNin et al, 2011). Taken together, these data suggest that TSPO ligands that stimulate Allo biosynthesis might have an advantage over BZDs in the treatment of psychiatric disorders in which neurosteroid down-regulation and changes in GABAA receptor expression are operative (Pinna and Rasmusson, 2012).…”

“…In clinical studies, decreases of Allo in the serum, plasma, and cerebrospinal fluid (CSF) content are associated with several psychiatric disorders, such as depression, anxiety, PTSD, schizophrenia and impulsive aggression (Uzunova et al, 1998;Rasmusson et al, 2006). Preclinical studies using socially isolated mice as an animal model of PTSD have also demonstrated that corticolimbic Allo levels become markedly decreased in association with the development of anxiety-like behaviours, resistance to sedation and extreme aggression (Pibiri et al, 2008;Nin et al, 2011;Pinna and Rasmusson, 2012). It is important to point out that SSRIs such as fluoxetine or norfluoxetine were able to reverse the decrease of brain neurosteroid levels (such as Allo) and to correct behavioural deficits expressed by socially isolated mice even at dosages that are 50-fold lower than those required to cause an effective 5-HT reuptake inhibition (Pinna et al, 2003(Pinna et al, , 2004a(Pinna et al, , 2009Pinna, 2010).…”

Free and Easy Wanderer Plus (FEWP) improves behavioral deficits in an animal model of post-traumatic stress disorder by stimulating allopregnanolone biosynthesis

“…Furthermore, our results are concordant with other studies showing that the anxiolytic, and anti-depressant effects were elicited by allopregnanolone [11,12]. Allopregnanolone normalized the exaggerated contextual fear responses and anxiety of socially isolated mice [13].…”

Involvement of pregnane xenobiotic receptor in mating-induced allopregnanolone formation in the midbrain and hippocampus and brain-derived neurotrophic factor in the hippocampus among female rats

“…For example, one such neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP; a.k.a. allopregnanolone), is increased in rat brain following exposure to acute challenges/stressors, such as swim stress (Barbaccia et al, 1996; Purdy et al, 1991; Vallée et al, 2000), but decreased with chronic stressors, such as social isolation (Agís-Balboa et al, 2007; Bortolato et al, 2011; Dong et al, 2001; Matsumoto et al, 1999; Nin et al, 2011; Pibiri et al, 2008; Pinna and Rasmusson, 2012; Serra et al, 2004). These and other data suggest that neurosteroids, such as 3α,5α-THP, may have an important role for regulating the stress response.…”