SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake.
Brain principal glutamatergic neurons synthesize 3alpha-hydroxy-5alpha-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABA(A) 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. Emotional-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of cortico-limbic 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 GABA(A) receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).
Pinna
Graziano
G
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States. gpinna@psych.uic.edu <gpinna@psych.uic.edu>
Costa
Erminio
E
Guidotti
Alessandro
A
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005473:Fluoxetine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019964:Mood Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011280:Pregnanolone / Q000096:biosynthesis* / Q000134:cerebrospinal fluid; D011963:Receptors, GABA-A / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012934:Social Isolation; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D005473:Fluoxetine; D011280:Pregnanolone; D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors; D005680:gamma-Aminobutyric Acid; C036139:norfluoxetine