The habenular G-protein–coupled receptor 151 regulates synaptic plasticity and nicotine intake

The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield approaches to treat nicotine addiction. Here we show th...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2020-03, Vol.117 (10), p.5502-5509
Main Authors: Antolin-Fontes, Beatriz, Li, Kun, Ables, Jessica L., Riad, Michael H., Görlich, Andreas, Williams, Maya, Wang, Cuidong, Lipford, Sylvia M., Dao, Maria, Liu, Jianxi, Molina, Henrik, Heintz, Nathaniel, Kenny, Paul J., Ibañez-Tallon, Ines
Format: Article
Language:English
Subjects:
Acetylcholine receptors (nicotinic)
Addictions
Adenosine monophosphate
Aversion
Behavioral plasticity
Biological Sciences
Cell lines
Clonal deletion
Cyclic AMP
G protein-coupled receptors
Habenula
Ion transport
Membranes
Neurotransmission
Nicotine
Phenotypes
Plasticity
Proteins
Receptors
Synaptic plasticity
Synaptic vesicles
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield approaches to treat nicotine addiction. Here we show that GPR151, an orphan G-protein–coupled receptor (GPCR) highly enriched in the habenula of humans and rodents, is expressed at presynaptic membranes and synaptic vesicles and associates with synaptic components controlling vesicle release and ion transport. Deletion of Gpr151 inhibits evoked neurotransmission but enhances spontaneous miniature synaptic currents and eliminates short-term plasticity induced by nicotine.We find that GPR151 couples to the G-alpha inhibitory protein Gαo1 to reduce cyclic adenosine monophosphate (cAMP) levels in mice and in GPR151-expressing cell lines that are amenable to ligand screens. Gpr151– knockout (KO) mice show diminished behavioral responses to nicotine and self-administer greater quantities of the drug, phenotypes rescued by viral reexpression of Gpr151 in the habenula. These data identify GPR151 as a critical modulator of habenular function that controls nicotine addiction vulnerability.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1916132117