Abstract
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.
Highlights
Opiate drugs, such as morphine, are effective analgesic agents that are used for treating many forms of acute and chronic pain
In accordance with previous findings [29,30], post hoc analysis indicated that both sham and ADX groups rendered dependent on morphine showed a significantly (p,0.001) lower weight gain (213.7565.0 g, n = 12; 3.8462.45 g, n = 13, respectively) than that observed in sham and ADX animals receiving placebo pellets (44.5861.7 g, n = 12; 49.5762.4 g, n = 12, respectively), which has been attributed to the reduced food intake observed in these animals [29]
It has been extensively described that addictive substances and chronic stressful stimuli increase the expression of the transcription factor DFosB in the main nuclei involved in their positive reinforcing effects [12,13,32,33], and it has been proposed that the persistent effects of DFosB on target genes might play an important role in the development of adaptations that characterize addiction [9,34]
Summary
Opiate drugs, such as morphine, are effective analgesic agents that are used for treating many forms of acute and chronic pain. 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 [1,2,3,4]. Of particular interest in the study of addiction is the Fos family of transcription factors. This family includes c-Fos, Fra and Fra-2, FosB and DFosB, a truncated splice variant of fulllength FosB [5]. In contrast to other members of the Fos family, DFosB is modestly induced in the brain after acute drug administration, but because of its unusual long half-life it persists for weeks, even months, after the cessation of drug use. DFosB levels gradually accumulate with repeated drug exposure [6,7], suggesting that DFosB could represent a mechanism by which drugs of abuse produce lasting changes in gene expression pattern long after the drug is withdrawn [8]
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