The many “Neurofaces” of Prohibitins 1 and 2: Crucial for the healthy brain, dysregulated in numerous brain disorders

Bernstein, Hans‐Gert; Keilhoff, Gerburg; Dobrowolny, Henrik; Kreutz, Michael R.; Steiner, Johann

doi:10.1016/j.jchemneu.2023.102321

Cited by 2 publications

(3 citation statements)

References 121 publications

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“…Chronic morphine administration disrupts mitochondrial respiration and restoring proper functioning attenuates opioid withdrawal [86]. Additionally, Phb1 , an analogue of Phb1l2 , has been implicated in mediating glutamatergic and dopaminergic neural transmission and becomes dysregulated in several disorders, including alcohol use disorder [85]. It is thus likely that opioid use results in dysregulation of Phb1l2 functioning and through glutamate and dopamine dependent processes affects motivation to obtain the drug.…”

Section: Discussionmentioning

confidence: 99%

“…Break point: The peak SNP for break point achieved during the progressive ratio test is unknown, however, it is in perfect LD with a causal coding variant for, Phb1I2, suggesting that this gene is likely a main contributor to the functional consequences of this locus. Phb1I2 is localized to both neuronal and nonneural cells types in the central nervous system and helps to maintain mitochondria respiration by attenuating reactive oxygen species which contribute to cellular dysfunction [85]. Chronic morphine administration disrupts mitochondrial respiration and restoring proper functioning attenuates opioid withdrawal [86].…”

Section: Gwasmentioning

confidence: 99%

“…PCP4 mediates calcium signaling and through downstream mechanisms also affects dopamine and acetylcholine signaling [76]. PCP4 levels are attenuated in postmortem tissue of individuals diagnosed with alcohol use disorder [77] as well as in the NAc of rats following 2-weeks of nicotine withdrawal [78]. PCP4 has also been linked to cigarette smoking (62).…”

Section: Gwasmentioning

confidence: 99%

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Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Kuhn,

Cannella,

Chitre

et al. 2024

Preprint

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The increased prevalence of opioid use disorder (OUD) world-wide has made it imperative to disentangle the biological mechanisms contributing to OUD propensity. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain under explored. In the current study, genome-wide association (GWAS) analysis on over 850 male and female heterogeneous stock rats were performed to identify genes underlying heroin-taking, refraining and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct behaviors contributing to OUD, an experimental design not easily achieved in human GWAS analysis, and not performed to date for OUD GWAS studies. Our findings show, akin to the human population, several heritable traits related with OUD. We also identified genetic variants associated with heroin consumption, escalation of intake, motivation to obtain heroin, and basal levels of analgesic threshold prior to heroin experience, which was behaviorally unrelated to the heroin behaviors. Several of the genes identified are known biomarkers of other substance use disorders and mediators of neurobiological mechanisms underlying addiction-related behaviors. These findings emphasize the need to assess the role of these genetic variants in OUD, thereby augmenting our understanding of risk factors and neurobiological processes associated with OUD vulnerability.

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Section: Discussionmentioning

confidence: 99%

Section: Gwasmentioning

confidence: 99%

Section: Gwasmentioning

confidence: 99%

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Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Kuhn,

Cannella,

Chitre

et al. 2024

Preprint

View full text Add to dashboard Cite

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Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Kuhn,

Cannella,

Chitre

et al. 2024

Preprint

View full text Add to dashboard Cite

The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. Tom1, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including Brwd1, Pcp4, Phb1l2 and Mmp15 were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats.

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The many “Neurofaces” of Prohibitins 1 and 2: Crucial for the healthy brain, dysregulated in numerous brain disorders

Cited by 2 publications

References 121 publications

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

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