Up-Regulation of Neurosteroid Biosynthesis as a Pharmacological Strategy to Improve Behavioural Deficits in a Putative Mouse Model of Post-Traumatic Stress Disorder

Benzodiazepines remain the most frequently used psychotropic drugs for the treatment of anxiety spectrum disorders; however, their use is associated with the development of tolerance and dependence. Another major hindrance is represented by their lack of efficacy in many patients, including patients with post-traumatic stress disorder (PTSD). For these nonresponders, the use of selective serotonin reuptake inhibitors (SSRIs) has been the therapy of choice. In the past decade, clinical studies have suggested that the pharmacological action of SSRIs may include the ability of these drugs to normalise decreased brain levels of neurosteroids in patients with depression and PTSD; in particular, the progesterone derivative allopregnanolone, which potently, positively and allosterically modulates the action of GABA at GABAA receptors. Preclinical studies using the socially-isolated mouse as an animal model of PTSD have demonstrated that fluoxetine and congeners ameliorate anxiety-like behaviour, fear responses and aggressive behaviour expressed by such mice by increasing corticolimbic levels of allopregnanolone. This is a novel and more selective mechanism than serotonin reuptake inhibition, which, for half a century, has been considered to be the main molecular mechanism for the therapeutic action of SSRIs. Importantly, this finding may shed light on the high rates of SSRI resistance among patients with PTSD and depression, comprising disorders in which there appears to be a block in allopregnanolone synthesis. There are several different mechanisms by which such a block may occur, and SSRIs may only be corrective under some conditions. Thus, the up-regulation of allopregnanolone biosynthesis in corticolimbic neurones may offer a novel nontraditional pharmacological target for a new generation of potent nonsedating, anxiolytic medications for the treatment of anxiety, depression, and PTSD: selective brain steroidogenic stimulants.