Research Article: Glucocorticoids Regulation of FosB/ΔFosB Expression Induced by Chronic Opiate Exposure in the Brain Stress System

Date Published: November 21, 2012

Publisher: Public Library of Science

Author(s): Daniel García-Pérez, M. Luisa Laorden, M. Victoria Milanés, Cristina Núñez, Yvette Tache.


Chronic use of drugs of abuse profoundly alters stress-responsive system. Repeated exposure to morphine leads to accumulation of the transcription factor ΔFosB, particularly in brain areas associated with reward and stress. The persistent effects of ΔFosB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that stress-related hormones (e.g., glucocorticoids, GC) may induce adaptations in the brain stress system that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FosB/ΔFosB in both hypothalamic and extrahypothalamic brain stress systems during morphine dependence. For that, expression of FosB/ΔFosB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made opiate dependent after ten days of morphine treatment. In sham-operated rats, FosB/ΔFosB was induced after chronic morphine administration in all the brain stress areas investigated: nucleus accumbens(shell) (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), hypothalamic paraventricular nucleus (PVN) and nucleus of the solitary tract noradrenergic cell group (NTS-A2). Adrenalectomy attenuated the increased production of FosB/ΔFosB observed after chronic morphine exposure in NAc, CeA, and NTS. Furthermore, ADX decreased expression of FosB/ΔFosB within CRH-positive neurons of the BNST, PVN and CeA. Similar results were obtained in NTS-A2 TH-positive neurons and NAc pro-dynorphin-positive neurons. These data suggest that neuroadaptation (estimated as accumulation of FosB/ΔFosB) to opiates in brain areas associated with stress is modulated by GC, supporting the evidence of a link between brain stress hormones and addiction.

Partial Text

Opiate drugs, such as morphine, are effective analgesic agents that are used for treating many forms of acute and chronic pain. However, serious adverse effects such as tolerance and withdrawal contribute to opiate dependence and limit their use. Further, the non-medical use of opiates (heroin, morphine) has increased during the past few years. Increasing evidence implicates various mechanisms of gene regulation (including epigenetic, molecular, cellular and circuit level effects) in the changes that drugs of abuse induce in the brain, indicating a potential therapeutic strategy for addiction therapy [1]–[4].

The current results indicated, for the first time, that brain GC signalling modulated chronic morphine administration-induced FosB/ΔFosB expression in the brain stress system in a region-specific manner.