Variants of κ-opioid receptor gene and mRNA in alcohol-preferring and alcohol-avoiding mice

Saito, Mariko; Ehringer, Marissa A.; Tóth, Réka; Oros, Melinda; Szakall, Istvan; Sikela, James M.; Vadász, Csaba

doi:10.1016/s0741-8329(02)00322-1

Cited by 27 publications

(27 citation statements)

References 34 publications

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“…Our recent results suggested that D1Mit167 in RQI strains cosegregated with markers located on chr. 5 (21), which is consistent with positions for D1Mit167 given by current databases (cf. The T31 Radiation Hybrid Maps Frameworked to TJL BSB / BSS Backcrosses; http://www.jax.org/resources/documents/cmdata/rhmap/maps/).…”

Section: Discussionsupporting

confidence: 89%

“…Our follow-up studies on opioid receptor kappa 1 knock-out mice indicated that complete constitutional dysfunction of the Oprk1 gene can reduce alcohol consumption (20), however chromosome position of microsatellite marker " D1Mit167" in the MIT database was assigned incorrectly, and the proposed chr. 1 region was not associated with genetic variation in alcohol consumption (21).…”

Section: Introductionmentioning

confidence: 89%

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Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

et al. 2007

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One strategy to identify neurochemical pathways of addiction is to map the relevant genes. In the present study we used 43 B6.C and 35 B6.I inbred RQI mouse strains, carrying <3% donor genome on C57BL/6ByJ background, for gene mapping. The strains were phenotyped for consumption of alcohol (12% v/v) in a two-bottle-choice paradigm, and genotyped for 396 microsatellite markers. The current mapping study extends our earlier experiment scanning five mouse chromosomes (1) to a whole-genome study, and discusses the differences and limitations. Data were analyzed with composite interval (CIM) and multiple interval (MIM) QTL mapping methods. CIM of B6.C strains detected significant QTLs on chrs. 6 and 12. A suggestive, but not significant, locus was detected in the B6.I strains on chr. 12. The best MIM model for B6.C strains confirmed one QTL on chr. 6 and one QTL on chr. 12., while the MIM model for the B6.I strains confirmed the suggestive locus on chr. 12. Some of the QTLs for alcohol consumption are new, while others confirm previously reported QTLs for alcohol preference, and alcohol acceptance.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 89%

Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

et al. 2007

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“…The current study, demonstrating experience-related plasticity of the KOR gene, is in line with previous reports showing changes in mRNA expression of KOR (14-16) and dynorphin (17,18) following the induction of behavioral stress or in stresssensitive rodent lines (19,20). However, different from most previous studies, the current research used a detailed assessment of the different KOR isoforms and polyadenylation sites in an attempt to take into account the complexity of this gene's regulatory elements conserved in human and mice (21,22).…”

Section: Discussionsupporting

confidence: 93%

“…Exposure to stress and recovery affects dynorphin and KOR mRNA levels in hypothalamus, hippocampus, striatum, and amygdala (14)(15)(16)(17)(18), and differential KOR mRNA levels were detected in stresssensitive rodent strains [Wistar-Kyoto rats (19), BALB/cJ, and DBA/2J mice (20)]. However, these results are complicated by inconsistent findings.…”

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confidence: 99%

“…By combining 5′ variation and alternative PA use, at least six RNA isoforms can be generated from the KOR gene, each with distinct stability, translation, and transport efficiency, providing a rich reservoir for regulating receptor production and/or distribution (23). The development of neuropathic pain following nerve injury correlates with differential expression of KOR mRNA isoforms (24), and rodent strains with elevated stress susceptibility (1) have differential expression of KOR mRNA isoforms in the cortex, hypothalamus, and locus coeruleus (19,20). It is possible that stress differentially modulates KOR gene regulation in stress-related brain areas in a specific manner.…”

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confidence: 99%

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Stress-induced epigenetic regulation of κ-opioid receptor gene involves transcription factor c-Myc

Flaisher-Grinberg

Persaud

Loh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Exposure to stress is associated with adverse emotional and behavioral responses. Whereas the κ-opioid receptor (KOR) system is known to mediate some of the effects, it is unclear whether and how stress affects epigenetic regulation of this gene. Because the KOR gene can use two promoters (Pr1 and Pr2) and two polyadenylation signals (PA1 and PA2), it is also interesting whether and how these distinct regulatory mechanisms are differentially modulated by stress. The current study examined the effects of stress on these different regulatory mechanisms of the KOR gene. Results showed that stress selectively increased the expression of KOR mRNA isoforms controlled by Pr1 and terminated at PA1 in specific brain areas including the medial-prefrontal cortex, hippocampus, brainstem, and sensorimotor cortex, but not in the amygdala or hypothalamus. These effects correlated with altered epigenetic state of KOR Pr1 chromatin, as well as elevation and increased recruitment of the principal transcription factor c-Myc, which could activate Pr1. Stress-induced modulation of Pr1 was further validated using glutamate-sensitive murine hippocampal cell line, HT22. The results revealed a common molecular mechanism underlying the effect of stress on selected chromatin regions of this gene at the cellular level and in the context of whole animal and identified a critical role for c-Myc in stress-triggered epigenetic regulation of the KOR gene locus. This study sheds light on the mechanisms of stress-induced epigenetic regulation that targets specific chromatin segments and suggests certain KOR transcripts and its principal transcription factor c-Myc as potential targets for brain-area-specific intervention.

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Human Kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction

Gerra¹,

Leonardi

Cortese

et al. 2007

American J of Med Genetics Pt B

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Variants of the opioid receptors are the obvious candidates underlying addiction. The kappa opioid receptor (KOR) system seems to play a role in stress responsivity, opiate withdrawal and responses to psycho-stimulants, inhibiting mesolimbic dopamine. KOR gene polymorphisms have been reported to contribute to predisposition to voluntary alcohol-drinking behavior in experimental animals. In humans, the 36G > T single nucleotide polymorphism (SNP) on KOR gene, that was recently identified, has been found associate with substance dependence, with inconclusive findings. In the present study, 106 heroin addicts (West European, Caucasians) and 70 healthy control subjects matched for race and gender, with no history of substance use disorder, have been genotyped. The frequency of KOR 36G > T SNP was significantly higher among heroin-dependent individuals compared with control subjects (Fisher's exact = 0.044; Pearson chi(2) = 4.2734, P = 0.039; likelihood ratio chi(2) tests = 4.6156, P = 0.032). Although KOR silent polymorphisms may apparently have no consequences on mRNA transcription, post-transcriptional mechanisms, such as mRNA stability, translation efficiency, and regulability may impair the function of kappa receptors system, with increased risk for substance use disorders. In specific, the neurobiological changes induced by mu-kappa opioid imbalance could underlie vulnerable personality traits and risk behavior.

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Variants of κ-opioid receptor gene and mRNA in alcohol-preferring and alcohol-avoiding mice

Cited by 27 publications

References 34 publications

Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

Stress-induced epigenetic regulation of κ-opioid receptor gene involves transcription factor c-Myc

Human Kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction

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