Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

Rodrigues, Ana João; Leão, Pedro; Pêgo, José M.; Cardona, Diana M.; Carvalho, M. Alice; Oliveira, Miguel; Costa, Bruno M.; Carvalho, Ana Raquel Franky Gomes; Morgado, Pedro; Araujo, Dalia M.; Palha, Joana Almeida; Almeida, Osborne F. X.; Sousa, Nuno

doi:10.1038/mp.2011.126

Cited by 47 publications

(77 citation statements)

References 52 publications

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“…D2 receptor (~47 kDa isoform) was increased in the mPFC (Figures 3c and d; U =0.0, P =0.01) and in the OFC (Figures 3g and h; U =0.0, P =0.004) of iuGC animals; these findings are in alignment with those previously reported for the NAc 13 and amygdala. 12 Conversely, we did not find changes in the D1 or D3 receptors in both the mPFC (Figures 3c and d) and the OFC (Figures 3g and h).…”

Section: Resultssupporting

confidence: 91%

“…Several studies focused on the structural, morphological and neurochemical changes that iuGC exposure causes in limbic regions; 11,13,31 however, less is known about the cortical regions that also receive dopaminergic transmission arising from the VTA. In the current study we analyzed the neuronal number and volume of the OFC subregions - lateral OFC and vOFC, and the mPFC subregions - ACC, PLC and ILC (Supplementary Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…13 Briefly, tissue was mechanically homogenized, centrifuged and the supernatant was quantified using the Bradford method. Fifty micrograms of the protein were run in SDS-polyacrylamide gel and transferred to nitrocellulose membranes.…”

Section: Methodsmentioning

confidence: 99%

“…11, 12, 13 As a result, these animals displayed persistent anhedonia but enhanced vulnerability for drug-seeking behavior in adulthood. 13,14 These symptoms may result from a complex differential attribution of incentive salience to natural versus non-natural rewards and their associated cues. In fact, individual differences in incentive salience attribution/'wanting' have been linked with propensity for addiction-like behaviors.…”

Section: Introductionmentioning

confidence: 99%

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The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure

et al. 2014

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Exposure to elevated levels of glucocorticoids (GCs) during neurodevelopment has been identified as a triggering factor for the development of reward-associated disorders in adulthood. Disturbances in the neural networks responsible for the complex processes that assign value to rewards and associated stimuli are critical for disorders such as depression, obsessive–compulsive disorders, obesity and addiction. Essential in the understanding on how cues influence behavior is the Pavlovian–instrumental transfer (PIT), a phenomenon that refers to the capacity of a Pavlovian stimulus that predicts a reward to elicit instrumental responses for that same reward. Here, we demonstrate that in utero exposure to GCs (iuGC) impairs both general and selective versions of the PIT paradigm, suggestive of deficits in motivational drive. The iuGC animals presented impaired neuronal activation pattern upon PIT performance in cortical and limbic regions, as well as morphometric changes and reduced levels of dopamine in prefrontal and orbitofrontal cortices, key regions involved in the integration of Pavlovian and instrumental stimuli. Normalization of dopamine levels rescued this behavior, a process that relied on D2/D3, but not D1, dopamine receptor activation. In summary, iuGC exposure programs the mesocorticolimbic dopaminergic circuitry, leading to a reduction in the attribution of the incentive salience to cues, in a dopamine-D2/D3-dependent manner. Ultimately, these results are important to understand how GCs bias incentive processes, a fact that is particularly relevant for disorders where differential attribution of incentive salience is critical.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure

et al. 2014

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“…Drug-and tissue-specific effects were also identified in the study by Tian et al [32] where global DNAm reductions were evident in the prefrontal cortex (but not in the nucleus accumbens) of mice exposed to cocaine (not heroin)-an effect that was reversible through repeated administration of methionine. With regard to candidate genes, increased Drd2 receptor methylation was observed in the nucleus accumbens of rats exposed to glucocorticoids in utero [33]. This association was specific to morphine administration and reversed by L-dopa treatment.…”

Section: Adulthoodmentioning

confidence: 80%

DNA Methylation, Substance Use and Addiction: a Systematic Review of Recent Animal and Human Research from a Developmental Perspective

2015

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Growing evidence points to the role of epigenetic mechanisms, including DNA methylation, in substance use and addiction. We conducted a systematic review of 47 recent (2012)(2013)(2014)(2015) animal and human studies that investigate DNA methylation and substance use/exposure, spanning preconception to adulthood. The majority of extant studies (i) focused on exposure during adulthood, (ii) examined the effects of alcohol use, (iii) employed a candidate gene approach, and (iv) were cross-sectional. While studies generally support an association between substance use/exposure and DNA methylation and also suggest that developmental context and timing matter, a dearth of longitudinal data and low comparability across studies currently limits the conclusions that can be drawn. Future challenges and directions for the field are discussed.

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Experience and the ever‐changing brain: What the transcriptome can reveal

2014

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The brain is an ever-changing organ that encodes memories and directs behavior. Neuroanatomical studies have revealed structural plasticity of neural architecture, and advances in gene expression technology and epigenetics have demonstrated new mechanisms underlying the brain’s dynamic nature. Stressful experiences challenge the plasticity of the brain, and prolonged exposure to environmental stress redefines the normative transcriptional profile of both neurons and glia, and can lead to the onset of mental illness. A more thorough understanding of normal and abnormal gene expression is needed to define the diseased brain and improve current treatments for psychiatric disorders. The efforts to describe gene expression networks have been bolstered by microarray and RNA-sequencing technologies. The heterogeneity of neural cell populations and their unique microenvironments, coupled with broad ranging interconnectivity, makes resolving this complexity exceedingly challenging and requires the combined efforts of single cell and systems level expression profiling to identify targets for therapeutic intervention.

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Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

Cited by 47 publications

References 52 publications

The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure

The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure

DNA Methylation, Substance Use and Addiction: a Systematic Review of Recent Animal and Human Research from a Developmental Perspective

Experience and the ever‐changing brain: What the transcriptome can reveal

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