Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography

Department of Psychiatry, University of Illinois at Chicago 60612, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/1996; 93(22):12599-604. DOI: 10.1073/pnas.93.22.12599
Source: PubMed
Fluoxetine administered intraperitoneally to sham-operated or adrenalectomized/castrated (ADX/CX) male rats dose-dependently (2.9-58 mumol/kg i.p.) increased the brain content of the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, 3 alpha, 5 alpha-TH PROG). The increase of brain 3 alpha, 5 alpha-TH PROG content elicited by 58 mumol/kg fluoxetine lasted more than 2 hr and the range of its extent was comparable in sham-operated (approximately 3-10 pmol/g) and ADX/CX rats (2-9 pmol/g) and was associated with a decrease (from 2.8 to 1.1 pmol/g) in the 5 alpha-pregnan-3,20-dione (5 alpha-dihydroprogesterone, 5 alpha-DH PROG) content. The pregnenolone, progesterone, and dehydroepiandrosterone content failed to change in rats receiving fluoxetine. The extent of 3 alpha, 5 alpha-TH PROG accumulation elicited by fluoxetine treatment differed in various brain regions, with the highest increase occurring in the olfactory bulb. Importantly, fluoxetine failed to change the 3 alpha, 5 alpha-TH PROG levels in plasma, which in ADX/CX rats were at least two orders of magnitude lower than in the brain. Two other serotonin re-uptake inhibitors, paroxetine and imipramine, in doses equipotent to those of fluoxetine in inhibiting brain serotonin uptake, were either significantly less potent than fluoxetine (paroxetine) or failed to increase (imipramine) 3 alpha, 5 alpha-TH PROG brain content. The addition of 10 microM of 5 alpha-DH PROG to brain slices of ADX/CX rats preincubated with fluoxetine (10 microM, 15 min) elicited an accumulation of 3 alpha, 5 alpha-TH PROG greater than in slices preincubated with vehicle. A fluoxetine stimulation of brain 3 alpha, 5 alpha-TH PROG biosynthesis might be operative in the anxiolytic and antidysphoric actions of this drug.

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    • "A more likely explanation for the effect of fluoxetine relates to its steroid-stimulating properties. Fluoxetine induces a rapid rise in brain concentration of allopregnanolone (Fry et al., 2014; Pinna et al., 2009; Uzunov et al., 1996). This steroid-stimulating effect occurs at doses below the threshold for actions on 5-HT systems (Devall et al., 2015; Pinna et al., 2009). "
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    • "Allopregnanolone and other neurosteroids are endogenously produced high-affinity ligands of GABA A Rs that dynamically potentiate the function of GABA similar to benzodiazepines. Significantly, chronic treatment with fluoxetine (but not imipramine) increased the allopregnanolone concentrations in rats and normalized its concentration in MDD patients (Uzunov, Cooper, Costa, & Guidotti, 1996; Uzunova et al., 1998 ). Collectively, it is becoming increasingly evident that antidepressant therapies, including drug therapies designed to normalize monoaminergic transmission, ultimately act to enhance GABAergic transmission. "
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    • "GABAergic transmission [25,26] and their levels are altered in individuals with a history of mania and bipolar disorder [27]. Psychiatric medications such as fluoxetine [28], lithium [29], clozapine [30] and olanzapine [31] have also been demonstrated to modulate neurosteroid levels. The DNA methylation changes we identified for the CYP11A1 locus are significantly correlated with several inflammatory markers suggesting a potential molecular basis for the association between inflammation and mania. "
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