Heydendael W, Jacobson L. Widespread hypothalamic-pituitary-adrenocortical axis-relevant and mood-relevant effects of chronic fluoxetine treatment on glucocorticoid receptor gene expression in mice. Eur J Neurosci 31: 892-902
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA. European Journal of Neuroscience
(Impact Factor: 3.18).
03/2010; 31(5):892-902. DOI: 10.1111/j.1460-9568.2010.07131.x
Tricyclic antidepressants (TCAs) have been used to treat melancholic depression, which has been associated with elevated hypothalamic-pituitary-adrenocortical (HPA) axis activity, whereas patients suffering from atypical depression, which is often associated with decreased HPA axis activity, show preferential responsiveness to monoamine oxidase inhibitors (MAOIs). We previously reported drug-specific effects of the TCA imipramine and the MAOI phenelzine on HPA axis-relevant endpoints in mice that may explain differential antidepressant responses in melancholic vs. atypical depression. However, selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in both melancholic and atypical depression. We therefore hypothesized that SSRIs would share HPA axis-related effects with either TCAs or MAOIs. To test this hypothesis, we measured HPA axis-relevant gene expression in male C57BL/6 mice treated for 5 weeks with 10 mg/kg/day fluoxetine. To control for potential fluoxetine-induced changes in glucocorticoid secretion, mice were adrenalectomized and given fixed levels of glucocorticoids. Fluoxetine decreased glucocorticoid receptor (GR) gene expression in the prefrontal cortex, amygdala, locus coeruleus and dorsal raphé nucleus, and increased locus coeruleus tyrosine hydroxylase and dorsal raphé nucleus tryptophan hydroxylase-2 (TPH2) gene expression. These results resembled those that we previously reported for MAOI treatment, but included decreases in GR and increases in TPH2 gene expression in the dorsal raphé nucleus that were induced by TCAs but not MAOIs. Correlating with inhibitory effects on central amygdala GR gene expression, fluoxetine also decreased amygdala corticotropin-releasing hormone gene expression, an effect not previously observed with MAOIs or TCAs. These actions may be relevant to the efficacy of SSRIs in treating a range of depression and anxiety disorders.
Available from: Predrag Jovanović
- "in cells, while VMAT2 is colocalized with TH enzyme (Tillinger et al. 2010). A subpopulation of chromogranin A -expressing chromaffin cells of the adrenal medulla also express VMAT2 (Weihe et al. 1994). Chromogranins are highly efficient systems directly involved in monoamine accumulation and in the exocytotic release of catecholamines (Borges et al. 2010)."
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ABSTRACT: We have recently shown that chronic fluoxetine treatment acted significantly increasing plasma norepinephrine and epinephrine concentrations both in control and chronically stressed adult male rats. However, possible effects of fluoxetine on catecholamine synthesis and re-uptake in adrenal medulla have been largely unknown. In the present study the effects of chronic fluoxetine treatment on tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis, as well as a norepinephrine transporter and vesicular monoamine transporter 2 gene expressions in adrenal medulla of animals exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, were investigated. Gene expression analyses were performed using a real-time quantitative reverse transcription-PCR. Chronically stressed animals had increased tyrosine hydroxylase mRNA levels and decreased expression of both transporters. Fluoxetine increased tyrosine hydroxylase and decreased norepinephrine transporter gene expression in both unstressed and CUMS rats. These findings suggest that chronic fluoxetine treatment increased plasma catecholamine levels by affecting opposing changes in catecholamine synthesis and uptake.
Available from: sciencedirect.com
- "inhibitory effects of antidepressant treatment on HPA activity have been reported, the literature is not consistent in this regard   . Because our previous data indicated that antidepressant effects on PFC GR expression were distributed across different PFC subdivisions  , we did not initially target individual regions of the prefrontal cortex. Selective knockdown of infralimbic vs. prelimbic PFC GR was reported during the completion of the current experiments to have differential effects on emotional behavior and HPA activity, with only infralimbic GR loss increasing depression-like behavior and augmenting the impact of chronic stress on HPA responses to a novel stimulus . "
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ABSTRACT: Our laboratory has previously shown that antidepressants regulate glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC). To determine if PFC GR are involved in antidepressant effects on behavior or hypothalamic–pituitary–adrenocortical (HPA) axis activity, we treated floxed GR male mice with saline or 15 or 30 mg/kg/d imipramine after PFC injection of adeno-associated virus 2/9 vectors transducing expression of Cre recombinase, to knock-down GR (PFC-GRKD), or green fluorescent protein (PFC-GFP), to serve as a control. The pattern of virally transduced GR deletion, common to all imipramine treatment groups, included the infralimbic, prelimbic, and medial anterior cingulate cortex at its largest extent, but was confined to the prelimbic and anterior cingulate cortex at its smallest extent. PFC GR knock-down increased behavioral sensitivity to imipramine, with imipramine-treated PFC-GRKD but not PFC-GFP mice exhibiting significant decreases in depression-like immobility during forced swim. PFC GR deletion did not alter general locomotor activity. The 30 mg/kg dose of imipramine increased plasma corticosterone levels immediately after a 5-min forced swim, but PFC GR knock-down had no significant effect on plasma corticosterone under these experimental conditions. We conclude that PFC GR knock-down, likely limited to the medial prelimbic and anterior cingulate cortices, can increase behavioral sensitivity to antidepressants. These findings indicate a novel role for PFC GR in influencing antidepressant response.
Available from: Yvet Kroeze
- "Starting at the level of the paraventricular nucleus (PVN) in the hypothalamus, male mice acutely treated with fluoxetine (10 mg/kg) exhibited no changes in arginine vasopressin (Avp), oxytocin (Oxt) and CRF mRNA expression , but female wild-type animals showed increased PVN Avp and Oxt mRNA levels (Stewart et al., 2008). Upon chronic fluoxetine treatment , amygdala CRF gene expression was decreased (Heydendael & Jacobson, 2010), and Brady et al. (1992) observed that chronic fluoxetine (5 mg/kg, i.p.) treatment for 2–8 weeks decreased CRF mRNA levels by 30–48% in the PVN of the hypothalamus. The decreases occurred at 8 weeks but not at 2 weeks. "
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ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed drugs in psychiatry. Based on the fact that SSRIs increase extracellular monoamine levels in the brain, the monoamine hypothesis of depression was introduced, postulating that depression is associated with too low serotonin, dopamine and noradrenaline levels. However, several lines of evidence indicate that this hypothesis is too simplistic and that depression and the efficacy of SSRIs are dependent on neuroplastic changes mediated by changes in gene expression. Because a coherent view on global gene expression is lacking, we aim to provide an overview of the effects of SSRI treatment on the final targets of 5-HT receptor signal transduction pathways, namely the transcriptional regulation of genes. We address gene polymorphisms in humans that affect SSRI efficacy, as well as in vitro studies employing human-derived cells. We also discuss the molecular targets affected by SSRIs in animal models, both in vivo and in vitro. We conclude that serotonin transporter gene variation in humans affects the efficacy and side-effects of SSRIs, whereas SSRIs generally do not affect serotonin transporter gene expression in animals. Instead, SSRIs alter mRNA levels of genes encoding serotonin receptors, components of non-serotonergic neurotransmitter systems, neurotrophic factors, hypothalamic hormones and inflammatory factors. So far little is known about the epigenetic and age-dependent molecular effects of SSRIs, which might give more insights in the working mechanism(s) of SSRIs.
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