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). "
[Show abstract][Hide abstract]ABSTRACT: Anxiety behavior in female Wistar rats was assessed at different stages of the estrous cycle using the elevated plus maze (EPM). No differences were observed at any cycle stage. Pretreatment with diazepam (1 mg kg(-1) intraperitoneal (i.p.)) 30 min before testing produced an anxiolytic effect (significant increase in percentage of time in the open arms compared to control group in the same cycle phase) in animals in proestrus, estrus, and early diestrus but had no effect in rats in late diestrus. Locomotor activity (total arm entries) was unchanged at any cycle phase. When rats in the late diestrus phase were pretreated with the selective serotonin reuptake inhibitor fluoxetine (1.75 mg kg(-1) i.p. on the afternoon of early diestrus and again in the morning of late diestrus) diazepam produced an anxiolytic effect (increase percentage time in the open arms). This dose is sufficient to raise brain allopregnanolone concentration without affecting 5-hydroxytryptamine (5-HT) systems. We propose that insensitivity to diazepam in late diestrus is due to increased expression of benzodiazepine insensitive α4 subunit-containing gamma-aminobutyric acid A (GABAA) receptors triggered by a sharp decrease in brain allopregnanolone concentration. Pretreatment with fluoxetine to raise brain allopregnanolone concentration during late diestrus prevents the withdrawal effect.
Full-text · Article · Mar 2016 · Journal of Psychopharmacology
"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. "
"GABAergic transmission [25,26] and their levels are altered in individuals with a history of mania and bipolar disorder . Psychiatric medications such as fluoxetine , lithium , clozapine  and olanzapine  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. "
[Show abstract][Hide abstract]ABSTRACT: In order to determine whether epigenetic changes specific to the manic mood state can be detected in peripheral blood samples we assayed DNA methylation levels genome-wide in serum samples obtained from 20 patients hospitalized for mania and 20 unaffected controls using the Illumina 450K methylation arrays. We identified a methylation locus in the CYP11A1 gene, which is regulated by corticotropin, that is hypo-methylated in individuals hospitalized for mania compared with unaffected controls. DNA methylation levels at this locus appear to be state related as levels in follow-up samples collected from mania patients six months after hospitalization were similar to those observed in controls. In addition, we found that methylation levels at the CYP11A1 locus were significantly correlated with three inflammatory markers in serum in acute mania cases but not in unaffected controls. We conclude that mania is associated with alterations in levels of DNA methylation and inflammatory markers. Since epigenetic markers are potentially malleable, a better understanding of the role of epigenetics may lead to new methods for the prevention and treatment of mood disorders.