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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    • "The concentration of neurosteroids present in vivo is not static but instead undergoes dynamic changes in response to various physiological and pathophysiological conditions including stress, pregnancy, the ovarian cycle and ageing (Purdy et al., 1991; Paul and Purdy, 1992; B€ ackstr€ om et al., 2003; Schumacher et al., 2003; Maguire and Mody, 2009; Sanna et al., 2009), as well as in response to administration of selected psychoactive drugs, such as ethanol, g-hydroxybutyrate (GHB) and anti-depressants including fluoxetine (Uzunov et al., 1996; Sanna et al., 2004). With this in mind, we performed similar experiments using varying concentrations of THDOC (0.1e100 nM) in order to establish whether PKC can reciprocally modulate the actions of neurosteroids across a range of concentrations. "
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    ABSTRACT: GABAA receptors are important for inhibition in the CNS where neurosteroids and protein kinases are potent endogenous modulators. Acting individually, these can either enhance or depress receptor function, dependent upon the type of neurosteroid or kinase and the receptor subunit combination. However, in vivo, these modulators probably act in concert to fine-tune GABAA receptor activity and thus inhibition, although how this is achieved remains unclear. Therefore, we investigated the relationship between these modulators at synaptic-type α1β3γ2L and extrasynaptic-type α4β3δ GABAA receptors using electrophysiology.
    Full-text · Article · Sep 2014 · Neuropharmacology
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    • "PregS also modulates synaptic transmission by both presynaptic and postsynaptic mechanisms across multiple neurotransmitter systems (reviewed in Zheng 2009). There are now many lines of evidence, both clinical and preclinical, linking neuroactive steroids to CNS disorders such as fetal alcohol spectrum disorder (Zimmerberg et al. 1995), epilepsy (Budziszewska et al. 1998; Hill et al. 2010; Pieribone et al. 2007), anxiety (Crawley et al. 1986; Ströhle et al. 2002), depression, and schizophrenia (Uzunov et al. 1996; Wolkowitz et al. 1999; Khisti et al. 2000; Marx et al. 2006; Girdler et al. 2012; Wong et al. 2012; Zorumski et al. 2013). Multiple potential targets for pharmacologic intervention by neuroactive steroids have been reviewed previously as well (Valenzuela et al. 2008; Zheng 2009; Reddy 2010; Marx et al. 2011). "
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    ABSTRACT: Rationale: The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects with reliable measurements of endogenous local concentrations and pharmacological and therapeutic targets has remained elusive for over 20 years. Objectives: New basic and clinical research concerning neurosteroid modulation of the central nervous system (CNS) function has emerged over the past 5 years, including important data involving pregnenolone and various neurosteroid precursors of PregS that point to a need for a critical status update. Results: Highly specific actions of PregS affecting excitatory N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and the pharmacological effects of PregS on various receptors and ion channels are discussed. The discovery of a high potency (nanomolar) signal transduction pathway for PregS-induced NMDAR trafficking to the cell surface via a Ca(2+)- and G protein-coupled receptor (GPCR)-dependent mechanism and a potent (EC50 ~ 2 pM) direct enhancement of intracellular Ca(2+) levels is discussed in terms of its agonist effects on long-term potentiation (LTP) and memory. Lastly, preclinical and clinical studies assessing the promnestic effects of PregS and pregnenolone toward cognitive dysfunction in schizophrenia, and altered serum levels in epilepsy and alcohol dependence, are reviewed. Conclusions: PregS is present in human and rodent brain at physiologically relevant concentrations and meets most of the criteria for an endogenous neurotransmitter/neuromodulator. PregS likely plays a significant role in modulation of glutamatergic excitatory synaptic transmission underlying learning and memory, yet the molecular target(s) for its action awaits identification.
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    • "The mechanism by which fluoxetine and other SSRIs (e.g. paroxetine) increase the levels of 5a3a-THPROG was initially postulated to involve modulation of 3a-HSD activity (Uzunov et al., 1996; Griffin and Mellon, 1999). However, a direct interaction between SSRIs and 3a-HSD remains controversial as subsequent studies failed to support the initial findings (Trauger et al., 2002). "
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    ABSTRACT: Regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity by stress is a fundamental survival mechanism and HPA-dysfunction is implicated in psychiatric disorders. Adverse early life experiences, e.g. poor maternal care, negatively influence brain development and programs an abnormal stress response by encoding long-lasting molecular changes, which may extend to the next generation. How HPA-dysfunction leads to the development of affective disorders is complex, but may involve GABAA receptors (GABAARs), as they curtail stress-induced HPA axis activation. Of particular interest are endogenous neurosteroids that potently modulate the function of GABAARs and exhibit stress-protective properties. Importantly, neurosteroid levels rise rapidly during acute stress, are perturbed in chronic stress and are implicated in the behavioral changes associated with early-life adversity. We will appraise how GABAAR-active neurosteroids may impact on HPA axis development and the orchestration of the stress-evoked response. The significance of these actions will be discussed in the context of stress-associated mood disorders.
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