SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake
Graziano Pinna, Erminio Costa, and Alessandro Guidotti
Brain principal glutamatergic neurons synthesize 3α-hydroxy-5α-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABAA receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Depression-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of corticolimbic Allo content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABAA receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).
Keywords: allopregnanolone, aggressive behavior, contextual fear conditioning, depression, PTSD, GABAA receptors, selective brain steroidogenic stimulants (SBSSs)