Nicotine self-administration and ERK signaling are altered in RasGRF2 knockout mice

Morella, Ilaria; Pohořalá, Veronika; Calpe-López, Claudia; Brambilla, Riccardo; Spanagel, Rainer; Bernardi, Rick E.

doi:10.3389/fphar.2022.986566

Cited by 5 publications

(3 citation statements)

References 68 publications

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“…Moreover, nicotine's ability to elevate ERK phosphorylation in the rat NAc has already been shown [40,41], thus supporting the role of this kinase in neuronal plasticity induced by nicotine dependence [42] regardless of the smoking device used.…”

Section: Discussionmentioning

confidence: 67%

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

Morosini,

Vivarelli,

Rullo

et al. 2024

IJMS

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Tobacco use disorder represents a significant public health challenge due to its association with various diseases. Despite awareness efforts, smoking rates remain high, partly due to ineffective cessation methods and the spread of new electronic devices. This study investigated the impact of prolonged nicotine exposure via a heat-not-burn (HnB) device on selected genes and signaling proteins involved in inflammatory processes in the rat ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions associated with addiction to different drugs, including nicotine. The results showed a reduction in mRNA levels for PPARα and PPARγ, two nuclear receptors and anti-inflammatory transcription factors, along with the dysregulation of gene expression of the epigenetic modulator KDM6s, in both investigated brain areas. Moreover, decreased PTEN mRNA levels and higher AKT phosphorylation were detected in the VTA of HnB-exposed rats with respect to their control counterparts. Finally, significant alterations in ERK 1/2 phosphorylation were observed in both mesolimbic areas, with VTA decrease and NAc increase, respectively. Overall, the results suggest that HnB aerosol exposure disrupts intracellular pathways potentially involved in the development and maintenance of the neuroinflammatory state. Moreover, these data highlight that, similar to conventional cigarettes, HnB devices use affects specific signaling pathways shaping neuroinflammatory process in the VTA and NAc, thus triggering mechanisms that are currently considered as potentially relevant for the development of addictive behavior.

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Section: Discussionmentioning

confidence: 67%

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

Morosini,

Vivarelli,

Rullo

et al. 2024

IJMS

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“…In conclusion, the monkey meta-analyzed data are in line with numerous publications showing the importance of the MAPK/ERK pathway in mediating acute and long-term effects of alcohol [64][65][66][67] . However, this is not an alcohol specific effect since reinforcing effects of other drugs of abuse, such as cocaine 68,69 and nicotine 70,71 are also mediated by this pathway. Therefore, clinically relevant, systemically administered drugs that target ERK signaling in the brain could be used to treat AUD and other substance use disorders 68 .…”

Section: Meta-analysis Of the Monkey Pfc Results In Alteration Of Map...mentioning

confidence: 99%

A Systematic Review and Meta-analysis on the Transcriptomic Signatures in Alcohol Use Disorder

Friske

Torrico

Borruto

et al. 2022

Preprint

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Alcohol Use Disorder (AUD) is a complex mental disease with a large treatment need. However, the clinically available therapeutic approaches are limited and thus new treatment targets are warranted. One approach to discover new treatment targets is transcriptomic profiling of key brain regions of the addiction neurocircuitry in animal models of AUD and/or in post-mortem brain tissue from deceased AUD patients. Unfortunately, those studies suffer from large heterogeneity and low sample sizes. Here we used a cross-species meta-analysis that integrates the entire literature on this topic to make more robust conclusions on transcriptomic changes in AUD. Here, we report on differentially expressed genes (DEGs) in 108 rat brain and 380 human brain samples, respectively in one of the key regions of AUD- the prefrontal cortex. We found 50 differentially expressed genes (DEGs) in rat brain, which were mainly associated with pro-oncogenic molecules, signal transduction as well as oxidative stress and inflammation. When we compared these findings with the meta-analytic results in human post-mortem PFC, we found that across species Hsd11b1 is significantly down-regulated. This finding is also confirmed by our cross-species data integrational approach. In summary, our data suggests that down-regulation of Hsd11b1 enzyme and stress-related pathways is a conserved mechanism for the alcohol dependent phenotype across different species, which might explain increased cortisol levels in AUD and therefore serves as a new treatment target.

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“…Moreover, RASGRF2 is implicated in various behavioral responses, including drug-related aversive and rewarding behaviors and contextual fear learning [ 25 , 26 , 27 ]. Certain haplotypes of RASGRF2 are linked to increased reward sensitivity and higher risk for alcohol use disorders [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Optical Genome Mapping Reveals Disruption of the RASGRF2 Gene in a Patient with Developmental Delay Carrying a De Novo Balanced Reciprocal Translocation

Lederbogen,

Hoffjan,

Thiels

et al. 2024

Genes

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While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation t(5;6)(q13;q23) between chromosomes 5 and 6 with limited resolution. Optical genome mapping (OGM) enabled a more precise depiction of the breakpoint regions involved in the reciprocal translocation. While the breakpoint region on chromosome 6 did not encompass any known gene, OGM revealed the disruption of the RASGRF2 (Ras protein-specific guanine nucleotide releasing factor 2) gene on chromosome 5, implicating RASGRF2 as a potential candidate gene contributing to the observed developmental delay in the patient. Variations in RASGRF2 have so far not been reported in developmental delay, but research on the RASGRF2 gene underscores its significance in various aspects of neurodevelopment, including synaptic plasticity, signaling pathways, and behavioral responses. This study highlights the utility of OGM in identifying breakpoint regions, providing possible insights into the understanding of neurodevelopmental disorders. It also helps affected individuals in gaining more knowledge about potential causes of their conditions.

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Nicotine self-administration and ERK signaling are altered in RasGRF2 knockout mice

Cited by 5 publications

References 68 publications

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

A Systematic Review and Meta-analysis on the Transcriptomic Signatures in Alcohol Use Disorder

Optical Genome Mapping Reveals Disruption of the RASGRF2 Gene in a Patient with Developmental Delay Carrying a De Novo Balanced Reciprocal Translocation

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