D3 dopamine receptors and a missense mutation of fatty acid amide hydrolase linked in mouse and men: implication for addiction.
Adult
Aged
Amidohydrolases
/ metabolism
Animals
Autoradiography
Brain
/ metabolism
Female
Gene Knock-In Techniques
Humans
Male
Mice
Middle Aged
Mutation, Missense
Polymorphism, Single Nucleotide
Positron-Emission Tomography
RNA, Messenger
/ metabolism
Receptors, Dopamine D3
/ genetics
Substance-Related Disorders
/ enzymology
Young Adult
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
12
10
2019
accepted:
19
11
2019
revised:
13
11
2019
pubmed:
28
11
2019
medline:
31
3
2021
entrez:
28
11
2019
Statut:
ppublish
Résumé
The endocannabinoid and dopaminergic systems have independently been implicated in substance use disorder and obesity. We investigated a potential interaction between genetically inherited variation in fatty acid amide hydrolase (FAAH, C385A), which metabolizes the cannabis-like endocannabinoid anandamide, and dopaminergic system, measured by dopamine receptor levels and mRNA. Binding of the dopamine D3 preferring probe [C-11]-(+)-PHNO was measured with positron emission tomography (PET) in 79 human subjects genotyped for the FAAH C385A polymorphism (36/79 AC + AA). Autoradiography with [H-3]-(+)-PHNO and in situ hybridization with a D3-specific S-35 riboprobe were carried out in 30 knock-in mice with the FAAH C385A polymorphism (20/30 AC + AA). We found that the FAAH genetic variant C385A was associated with significantly higher (+)-PHNO binding in both humans and in knock-in mice, and this effect was restricted to D3 selective brain regions (limbic striatum, globus pallidus, and ventral pallidum (9-14%; p < 0.04) in humans and Islands of Calleja (28%; p = 0.036) in mice). In situ hybridization with a D3-specific S-35 riboprobe in FAAH knock-in C385A mice confirmed significantly increased D3 receptor mRNA across examined regions (7-44%; p < 0.02). The association of reduced FAAH function with higher dopamine D3 receptors in human and mouse brain provide a mechanistic link between two brain systems that have been implicated in addiction-risk. This may explain the greater vulnerability for addiction and obesity in individuals with C385A genetic variant and by extension, suggest that a D3 antagonism strategy in substance use disorders should consider FAAH C385A polymorphism.
Identifiants
pubmed: 31775159
doi: 10.1038/s41386-019-0580-8
pii: 10.1038/s41386-019-0580-8
pmc: PMC7075906
doi:
Substances chimiques
DRD3 protein, human
0
RNA, Messenger
0
Receptors, Dopamine D3
0
Amidohydrolases
EC 3.5.-
fatty-acid amide hydrolase
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
745-752Subventions
Organisme : CIHR
ID : BSB-389329
Pays : Canada
Organisme : CIHR
ID : BSB-389342
Pays : Canada
Organisme : CIHR
ID : FDN-154294
Pays : Canada
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