The Glucocorticoid Receptor as a Potential Target to Reduce Cocaine Abuse

Abstract

Several findings suggest that glucocorticoid hormones are involved in determining the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor. In this study, we show that the selective inactivation of the GR gene in the brains of mice profoundly flattened the dose-response function for cocaine intravenous self-administration and suppressed sensitization, two experimental procedures considered relevant models of addiction. Furthermore, administration of a GR antagonist dose-dependently reduced the motivation to self-administer cocaine. Importantly, the absence of GR did not modify the basal behavioral and molecular effects of cocaine but selectively modified the excessive response to the drug spontaneously present in certain vulnerable individuals or induced by repeated drug exposure in others. In conclusion, we provide the first genetic evidence that the GR gene can modulate cocaine abuse. This suggests that targeting GR function in the brain could provide new therapeutic strategies to treat cocaine addiction for which there is no available treatment.

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

“…The anti-GC activity of mifepristone has made it a potential treatment for Cushing's syndrome (Johanssen and Allolio, 2007) and neurological and psychological disorders (DeBattista and Belanoff, 2006;Gallagher and Young, 2006;Gallagher et al, 2005Gallagher et al, , 2008Wulsin et al, 2010;Young, 2006). The drug has also been examined in the self-administration of amphetamine (De Vries et al, 1996), cocaine (Deroche-Gamonet et al, 2003;Fiancette et al, 2010), morphine (Mesripour et al, 2008), and ethanol, where it has been shown to have either no effect or decrease baseline ethanol consumption (Fahlke et al, 1995;Jacquot et al, 2008;Koenig and Olive, 2004;Lowery et al, 2010;O'Callaghan et al, 2005;Roberts et al, 1995;Yang et al, 2008). However, the role of mifepristone in stress-induced reinstatement of ethanol-seeking is not known.…”

Adrenal Activity during Repeated Long-Access Cocaine Self-Administration is Required for Later CRF-Induced and CRF-Dependent Stressor-Induced Reinstatement in Rats

“…We have found that the augmentation of CRF-independent cocaine-induced reinstatement after longaccess SA is also prevented by pre-SA ADX/C (Mantsch et al, 2008b), suggesting that adrenal-dependent adaptations in brain regions that represent a final common pathway for stimuli that induce cocaine seeking may underlie augmented reinstatement. Accordingly, it has been reported that glucocorticoid receptors in dopaminoceptive neurons, likely in the nucleus accumbens, contribute to drug seeking following repeated cocaine delivery, but are not necessary for responses to acute cocaine (Deroche-Gamonet et al, 2003;Ambroggi et al, 2009). …”

Le point sur l’addiction à la cocaïne et au crack

“…Ainsi, chez la souris, il semblerait que l'action sur les récepteurs aux glucocorticoïdes pourrait être un traitement de la dépendance à la cocaïne, notamment par une action sur les hormones du stress, un des facteurs identifiés en clinique comme pouvant induire un « craving », chez les usagers de cocaïne et de crack [13]. Une autre étude, chez le rat, a montré qu'un antagoniste aux cannabinoïdes, le SR141716A, ou rimonabant, était efficace pour réduire l'envie de consommer de la cocaïne [12,28], par un mécanisme agoniste GABAergique indirect.…”