Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder.
Animals
Base Sequence
Behavior, Animal
/ drug effects
Chromatin
/ metabolism
Corpus Striatum
/ enzymology
Cues
Genome
HEK293 Cells
Heroin
/ adverse effects
Heroin Dependence
/ enzymology
Humans
Male
Molecular Targeted Therapy
Neurons
/ metabolism
Phosphorylation
/ drug effects
Promoter Regions, Genetic
/ genetics
Proto-Oncogene Proteins c-fyn
/ antagonists & inhibitors
Rats, Long-Evans
Self Administration
Transcription, Genetic
/ drug effects
tau Proteins
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 09 2020
14 09 2020
Historique:
received:
05
07
2019
accepted:
04
08
2020
entrez:
15
9
2020
pubmed:
16
9
2020
medline:
24
9
2020
Statut:
epublish
Résumé
The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.
Identifiants
pubmed: 32929078
doi: 10.1038/s41467-020-18114-3
pii: 10.1038/s41467-020-18114-3
pmc: PMC7490718
doi:
Substances chimiques
Chromatin
0
tau Proteins
0
Heroin
70D95007SX
Proto-Oncogene Proteins c-fyn
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4634Subventions
Organisme : NIA NIH HHS
ID : R01 AG050986
Pays : United States
Organisme : NIDA NIH HHS
ID : P01 DA047233
Pays : United States
Organisme : NIDA NIH HHS
ID : R56 DA015446
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA015446
Pays : United States
Organisme : NIDA NIH HHS
ID : F30 DA038954
Pays : United States
Organisme : BLRD VA
ID : I01 BX002395
Pays : United States
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH109677
Pays : United States
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