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.
Highlights
We found that allopregnanolone levels and brain-derived neurotrophic factor (BDNF) mRNA expression are downregulated in the same brain areas, namely the medial frontal cortex, hippocampus, and BLA and fail to change in the cerebellum and striatum (Pibiri et al, 2008; Nelson et al, 2010)
We have observed that socially isolated mice, in addition to expressing a neurosteroidogenic deficit, which results in decreased levels of allopregnanolone, the most potent physiological positive modulator of GABAA receptor neurotransmission, express a BDNF level downregulation in corticolimbic neurons
Treatment with allopregnanolone or with non-serotonergic doses of fluoxetine and norfluoxetine normalized both the levels of www.frontiersin.org corticolimbic allopregnanolone and the mRNA expression of BDNF, which is associated with antianxiety and antiaggressive action as well as improvement of fear conditioning responses
Summary
Impaired neurosteroid biosynthesis has been associated with numerous behavioral dysfunctions, which range from anxietyand depressive-like behaviors to aggressive behavior and changes in responses to contextual fear conditioning in rodent models of emotional dysfunction (Pinna et al, 2003, 2004, 2006, 2008; Uzunova et al, 2004, 2006; Jain et al, 2005; Martin-Garcia and Pallares, 2005; Kita and Furukawa, 2008; D’Aquila et al, 2010; Pinna, 2010). BEHAVIORAL DYSFUNCTIONS ASSOCIATED WITH SOCIAL ISOLATION Exposure of mice or rats to protracted social isolation stress for 4–8 weeks induces a decrease in allopregnanolone levels in several corticolimbic structures as a result of a downregulation of the mRNA and protein expression of 5α-reductase type I (Matsumoto et al, 1999; Serra et al, 2000; Pinna et al, 2003; Bortolato et al, 2011; reviewed in Matsumoto et al, 2007; Pinna, 2010). Fluoxetine dose-dependently and stereospecifically normalized the duration of pentobarbital-induced sedation and reduced aggressiveness, fear responses, and anxiety-like behavior at the same submicromolar doses that normalized the downregulation of brain allopregnanolone content in socially isolated mice (Pinna et al, 2003, 2004, 2006, 2008, 2009). These studies suggest that part of the immediate or the long-term behavioral effects exerted by steroidogenic antidepressants may be explained by the effects of these drugs on allopregnanolone neosynthesis, which in turn may upregulate BDNF content and expression in corticolimbic neurons
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