Upregulation of neurosteroid biosynthesis as a pharmacological strategy to improve behavioral deficits in a putative mouse model of PTSD

摘要

Benzodiazepines remain the most frequently used psychotropic drugs for the treatment of anxiety spectrum disorders; however their use is associated with development of tolerance and dependence. Another major hindrance is represented by their lack of efficacy in many patients, including patients with posttraumatic stress disorder (PTSD). For these non-responders, 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 normalize decreased brain levels of neurosteroids in patients with depression and PTSD, in particular the progesterone derivative allopregnanolone, which potently 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 behavior, fear responses, and aggressive behavior expressed by such mice by increasing corticolimbic levels of allopregnanolone. This is a novel and more selective mechanism than 5-HT reuptake inhibition, which for half a century has been thought 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, 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, upregulation of allopregnanolone biosynthesis in corticolimbic neurons may offer a novel non-traditional pharmacological target for a new generation of potent non-sedating, anxiolytic medications for the treatment of anxiety, depression, and PTSD: selective brain steroidogenic stimulants (SBSSs).