VGLUT3 rare mutant and vulnerability to addiction


Addiction is a disease of reward system involving a combination of genetic and environmental factors. The nucleus accumbens (NAc) and dopamine (DA) signaling are pivotal in reward behavior and addiction. We recently established that DA signaling in the NAc is controlled by cholinergic interneurons, also named tonically active neurons or TANs. TANs express both the vesicular acetylcholine transporter (VAChT) and the atypical vesicular glutamate transporter VGLUT3. Therefore they communicate with acetylcholine (ACh) and glutamate. Mice lacking VGLUT3 have an increased DA tone in the NAc and are more sensitive to rewarding properties of cocaine. In addition the frequency of rare mutations of VGLUT3 is significantly increased in human with severe addictions. In particular, we identified one of these variations, VGLUT3-p.T8I, in several subjects with severe addictions. The aim of the ADIKHUMICE proposal is to establish whether the p.T8I mutation is causal in addiction and what are the underlying mechanisms. In that goal we will perform cellular, animal and clinical investigations. We will explore human neuronal culture and a mouse line expressing VGLUT3-p.T8I with electrophysiological, biochemical and behavioral methods. In addition, addicted patients carrying the VGLUT3-p.T8I allele will undergo a complete clinical phenotyping. This multi-disciplinary approach will increase our understanding of mechanisms underlying genetic vulnerability to addiction.


Autism, Pharmacology, Electrophisiological approaches, metabotropic glutamate receptors, Behavioural methodologies, amygdala, drug design, photopharmacology

Call topic

Synaptic Dysfunction

Proposed runtime

2018 - 2021

Project team

Salah El Mestikawy (Coordinator)
Canada (FRQS)
Stephane Jamain
France (ANR)
Florence Vorspan
France (ANR)
Rafael Maldonado
Spain (MINECO)
Christian Rosenmund
Germany (BMBF)