Corticosteroid receptor genes and childhood neglect influence susceptibility to crack/cocaine addiction and response to detoxification treatment

Rovaris, Diego Luiz; Mota, Nina Roth; Bertuzzi, Guilherme Pinto; Aroche, Angelita P.; Callegari-Jacques, Sídia M.; Guimarães, Luciano Santos Pinto; Pezzi, Júlio Carlos; Viola, Thiago Wendt; Bau, Claiton H.D.; Grassi‐Oliveira, Rodrigo

doi:10.1016/j.jpsychires.2015.06.008

Cited by 27 publications

(17 citation statements)

References 86 publications

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“…Genetic variation in the mineralocorticoid gene has been shown to interact with early environmental factors in disorders such as depression (Vogel et al, 2014;Vrijsen et al, 2015) and addiction (Rovaris et al, 2015). Although we did not find a gene-early environment interaction effect on behavioral measures such as maternal care, the increased basal corticosterone levels in MR +/− mice that experienced early-life adversity do support interaction effects.…”

Section: Gene-environment Interactioncontrasting

confidence: 74%

The effects of different rearing conditions on sexual maturation and maternal care in heterozygous mineralocorticoid receptor knockout mice

Knop

IJzendoorn

Bakermans‐Kranenburg

et al. 2019

Hormones and Behavior

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Sexual and social development is affected by a complex interplay between genetic makeup and the early-life rearing environment. While many rodent studies focused primarily on the detrimental effects of early-life stress, human literature suggests that genetic susceptibility may not be restricted to negative environments; it may also enhance the beneficial effects of positive rearing conditions. To examine this interaction in a controlled setting, heterozygous mineralocorticoid receptor knockout (MR +/−) mice and control litter mates were exposed to a limited nesting/bedding (LN, impoverished), standard nesting (SN, control) or communal nesting (CN, enriched) paradigm from postnatal day 2-9 (P2-P9). Offspring was monitored for puberty onset between P24-P36 and, in females, maternal care-giving (i.e. as F1) during adulthood, after which basal corticosterone was measured. Different home-cage environments resulted in profound differences in received maternal care and offspring body weight. In male offspring, LN resulted in delayed puberty onset that was mediated by body weight and unpredictability of maternal care received during early development. In female offspring, rearing condition did not significantly alter sexual maturation and had little effect on their own maternal care-giving behavior. Genotype did affect maternal care: female MR +/− offspring exhibited a less active nursing style and upregulated fragmentation during adulthood, irrespective of early life conditions. Basal corticosterone levels were highest in MR +/− mice with a background of LN. Overall, we found a gene-by-environment interaction with respect to basal corticosterone levels, but not for sexual maturation or maternal behavior.

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Section: Gene-environment Interactioncontrasting

confidence: 74%

The effects of different rearing conditions on sexual maturation and maternal care in heterozygous mineralocorticoid receptor knockout mice

Knop

IJzendoorn

Bakermans‐Kranenburg

et al. 2019

Hormones and Behavior

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“…The laboratory of Dr. Claiton H. D. Bau, at the Universidade Federal do Rio Grande do Sul in Porto Alegre, Brazil, has been a steady source of studies on the interaction between stress and different relevant genes to the risk of addiction. Rovaris et al (2015), from Bau’s team, set out to explore the connection between early life stress, genetic variants of MR and GR receptors, and risk of crack/cocaine addiction, in a genetic association study (Rovaris et al, 2015). They reported an interesting gene–environment interaction between high levels of childhood physical neglect and the rs5522-Val allele of the MR gene ( NR3C2 ), which very significantly modulated cocaine addiction severity.…”

Section: Latin American Non-clinical Studies and Translational Effortsmentioning

confidence: 99%

Interaction Between Stress and Addiction: Contributions From Latin-American Neuroscience

et al. 2018

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Drug addiction is a chronic neuropsychiatric disorder that escalates from an initial exposure to drugs of abuse, such as cocaine, cannabis, or heroin, to compulsive drug-seeking and intake, reduced ability to inhibit craving-induced behaviors, and repeated cycles of abstinence and relapse. It is well-known that chronic changes in the brain’s reward system play an important role in the neurobiology of addiction. Notably, environmental factors such as acute or chronic stress affect this system, and increase the risk for drug consumption and relapse. Indeed, the HPA axis, the autonomic nervous system, and the extended amygdala, among other brain stress systems, interact with the brain’s reward circuit involved in addictive behaviors. There has been a growing interest in studying the molecular, cellular, and behavioral mechanisms of stress and addiction in Latin-America over the last decade. Nonetheless, these contributions may not be as strongly acknowledged by the broad scientific audience as studies coming from developed countries. In this review, we compile for the first time a series of studies conducted by Latin American-based neuroscientists, who have devoted their careers to studying the interaction between stress and addiction, from a neurobiological and clinical perspective. Specific contributions about this interaction include the study of CRF receptors in the lateral septum, investigations on the neural mechanisms of cross-sensitization for psychostimulants and ethanol, the identification of the Wnt/β-catenin pathway as a critical neural substrate for stress and addiction, and the emergence of the cannabinoid system as a promising therapeutic target. We highlight animal and human studies, including for instance, reports coming from Latin American laboratories on single nucleotide polymorphisms in stress-related genes and potential biomarkers of vulnerability to addiction, that aim to bridge the knowledge from basic science to clinical research.

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“…One study found a gene–gene interaction of the NR3C1 SNP rs6198 and the NR3C2 SNP rs5522 on the severity of withdrawal symptoms, with lowest values in carriers of both minor alleles (Rovaris et al . ). Recently, the same group reported an effect of the NR3C1 SNP rs41423247 with an increase in depressive symptoms at early abstinence in the female carriers of the minor allele (Rovaris et al .…”

Section: Introductionmentioning

confidence: 97%

“…; Rovaris et al . ). Here, we therefore investigated rs10052957 ( TthIII l), rs10482605 ( NR3C1‐I ), rs6189/rs6190 ( ER22/23EK ), rs56149945 ( N363S ), rs41423247 ( Bcl I) and rs6198 ( GR9beta ), as well as the consequential five most frequent (>2 percent) haplotypes.…”

Section: Introductionmentioning

confidence: 97%

Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use

et al. 2018

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Animal and cross-sectional human studies suggest that chronic cocaine use is associated with altered responsivity of the hypothalamic-pituitary-adrenal axis to stress. Moreover, increased susceptibility to stress has been proposed as an important factor for development, maintenance and relapse of cocaine addiction. As the glucocorticoid receptor gene (NR3C1) mediates genomic effects of the stress hormone cortisol, we investigated NR3C1 expression and the association of NR3C1 genotypes with cocaine use, addiction and comorbid psychiatric symptoms in 126 chronic cocaine users and 98 stimulant-naïve healthy controls. A comprehensive psychiatric assessment was performed including severity of depressive symptoms and current psychological distress. Whole blood NR3C1 mRNA levels were determined and six NR3C1 polymorphisms (rs10482605, rs41423247, rs10052957, rs6189, rs56149945 and rs6198) were genotyped. Compared to controls, cocaine users showed significantly lower NR3C1 expression (P < 0.001), which was not affected by NR3C1 genotypes. In controls, rs41423247 [P < 0.01, false discovery rate (FDR)-corrected], haplotype 2 and haplotype 3 (both P < 0.05, FDR-corrected) were associated with altered NR3C1 gene expression. Haplotype 3 (including minor alleles of rs10052957 and rs41423247) was associated with an increased risk for cocaine addiction (odds ratio = 2.74, P < 0.05, uncorrected). Moreover, addicted cocaine users carrying haplotype 3 showed higher depression scores (P < 0.01, FDR-corrected) than noncarriers. Considering possible confounding effects of alcohol and/or depression, we conclude that chronic cocaine use is associated with lower NR3C1 gene expression suggesting possible direct effects of the drug on the biological adaptation of stress-related genes. Finally, we postulate that haplotype 3 of NR3C1 might serve as a potential risk factor for stimulant addiction and associated psychiatric symptoms.

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Corticosteroid receptor genes and childhood neglect influence susceptibility to crack/cocaine addiction and response to detoxification treatment

Cited by 27 publications

References 86 publications

The effects of different rearing conditions on sexual maturation and maternal care in heterozygous mineralocorticoid receptor knockout mice

The effects of different rearing conditions on sexual maturation and maternal care in heterozygous mineralocorticoid receptor knockout mice

Interaction Between Stress and Addiction: Contributions From Latin-American Neuroscience

Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use

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