, Volume 186, Issue 3, pp 362–372 | Cite as

Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake

  • Graziano Pinna
  • Erminio Costa
  • Alessandro Guidotti


It has recently become more clearly understood that in human brain pathophysiology, neurosteroids play a role in anxiety disorders, premenstrual syndrome, postpartum depression, posttraumatic stress disorder, and depression. In the treatment of major depression, recent clinical studies indicate that the pharmacological profiles of fluoxetine and fluvoxamine are correlated with the ability of these drugs to increase the brain and cerebrospinal fluid content of allopregnanolone (Allo), a potent positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors. Thus, the neurosteroid-induced positive allosteric modulation of GABA action at GABAA receptors is facilitated by fluoxetine or its congeners (i.e., paroxetine, fluvoxamine, sertraline), which may not block 5-HT reuptake at the doses currently prescribed in the clinic. However, these doses are effective in the treatment of premenstrual dysphoria, anxiety, and depression. In socially isolated mice, we tested the hypothesis that fluoxetine, norfluoxetine, and other specific serotonin reuptake inhibitor (SSRI) congeners stereoselectively upregulate neurosteroid content at doses insufficient to inhibit 5-HT reuptake; although they potentiate pentobarbital-induced sedation and exert antiaggressive action. Very importantly, the inhibition of 5-HT reuptake lacks stereospecificity and requires fluoxetine and norfluoxetine doses that are 50-fold greater than those required to increase brain Allo content, potentiate the action of pentobarbital, or antagonize isolation-induced aggression. Based on these findings, it could be inferred that the increase of brain Allo content elicited by fluoxetine and norfluoxetine, rather than the inhibition selective of 5-HT reuptake, may be operative in the fluoxetine-induced remission of the behavioral abnormalities associated with mood disorders. Therefore, the term “SSRI” may be misleading in defining the pharmacological profile of fluoxetine and its congeners. To this extent, the term “selective brain steroidogenic stimulants” (SBSSs) could be proposed.


Allopregnanolone Testosterone 5α-reductase type I SSRIs Aggressive behavior GABAA receptors Social isolation Premenstrual dysphoria Anxiety Depression 



This study was supported by National Institute of Mental Health Grants MH 56890 (to AG) and MH 071667 (to EC) and by a Campus Research Board Award 2-611185 (to GP).


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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Graziano Pinna
    • 1
  • Erminio Costa
    • 1
  • Alessandro Guidotti
    • 1
  1. 1.Psychiatric Institute, Department of Psychiatry, College of MedicineUniversity of Illinois at ChicagoChicagoUSA

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