A correlative study of RU38486 biopotency and competition with [3H]dexamethasone for receptors in the rat central nervous system

Allen, BG; Sutanto, W.; Jones, Melvyn

doi:10.1016/0022-4731(88)90133-1

Cited by 17 publications

(5 citation statements)

References 20 publications

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“…Mifepristone has somewhat limited blood-brain barrier permeability, but the concentrations attained in the brain are still significant (almost one-third those of serum; Heikinheimo and Kekkonen, 1993). Accordingly, systemic mifepristone administration produces behavioral changes (Roberts et al, 1995; Koenig and Olive, 2004; Simms et al, 2011), inhibits neurogenesis (Oomen et al, 2007), and, most directly, competes with dexamethasone for binding sites in the rat central nervous system (Allen et al, 1988). Our results likewise suggest that mifepristone reaches central GRs at concentrations sufficient for receptor occupancy.…”

Section: Discussionmentioning

confidence: 99%

Corticosteroid-Dependent Plasticity Mediates Compulsive Alcohol Drinking in Rats

Vendruscolo

Barbier

Schlosburg³

et al. 2012

J. Neurosci.

302

309

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Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharinsweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.

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Section: Discussionmentioning

confidence: 99%

Corticosteroid-Dependent Plasticity Mediates Compulsive Alcohol Drinking in Rats

Vendruscolo

Barbier

Schlosburg³

et al. 2012

J. Neurosci.

302

309

View full text Add to dashboard Cite

show abstract

“…Mifepristone or its vehicle (0.05% Tween 80 in distilled water) were given as a single dose intraperitoneally, immediately prior to withdrawal of the alcohol in all experiments. The dose for the majority of the experiments was 50 mg/kg, which has been previously shown to prevent the effects of exposure to chronic unpredictable stress in vivo on hippocampal calcium currents recorded subsequently in vitro (Moldow et al., 2005), to prevent the reduction of neurogenesis in rats caused by chronic corticosterone administration (Meyer et al., 2006) and to prevent binding of dexamethasone to the Type II glucocorticoid receptor (Allen et al., 1988), while a 40 mg/kg dose was found to prevent the facilitation of long term depression (LTD) caused in hippocampal neurons by restraint stress (Chaouloff et al., 2007). In the odor habituation and discrimination test the dose was lowered to 25 mg/kg in order to see whether or not the previously demonstrated effect of mifepristone in the object recognition experiments was seen using a lower mifepristone dose and a different memory test.…”

Section: Methodsmentioning

confidence: 99%

Effects of the Glucocorticoid Antagonist, Mifepristone, on the Consequences of Withdrawal From Long Term Alcohol Consumption

Jacquot

Croft

Prendergast

et al. 2008

Alcoholism Clin & Exp Res

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“…The GR and MR are also both able to bind the synthetic glucocorticoid, dexamethasone (DEX). However, unlike the endogenous glucocorticoids, DEX has greater preference for binding for the GR over the MR (Allen et al, 1988; Brinton and McEwen, 1988; Burgess and Handa, 1992). RU28362 is another synthetic glucocorticoid, but it is a selective agonist for the GR, with no apparent binding affinity for the MR (Coirini et al, 1985; Philibert and Moguilewsky, 1983; Quirk and Funder, 1988), and a Kd for the GR in the low nanomolar range.…”

Section: Mineralocorticoid and Glucocorticoid Receptorsmentioning

confidence: 99%

Gonadal steroid hormones and the hypothalamo–pituitary–adrenal axis

Handa

Weiser

2014

Frontiers in Neuroendocrinology

343

282

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The hypothalamo-pituitary-adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, prior to generating an appropriate response is the animal’s reproductive status. Thus, PVN neurons express androgen and estrogen receptors and receive input from sites that also express these receptors. Consequently, changes in reproduction and gonadal steroid levels modulate the stress response and this underlies sex differences in HPA axis function. This review examines the make up of the HPA axis and hypothalamopituitary-gonadal (HPG) axis and the interactions between the two that should be considered when exploring normal and pathological responses to environmental stressors.

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A correlative study of RU38486 biopotency and competition with [3H]dexamethasone for receptors in the rat central nervous system

Cited by 17 publications

References 20 publications

Corticosteroid-Dependent Plasticity Mediates Compulsive Alcohol Drinking in Rats

Corticosteroid-Dependent Plasticity Mediates Compulsive Alcohol Drinking in Rats

Effects of the Glucocorticoid Antagonist, Mifepristone, on the Consequences of Withdrawal From Long Term Alcohol Consumption

Gonadal steroid hormones and the hypothalamo–pituitary–adrenal axis

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