Research Highlight: Neuronal bilingualism regulates reward and addiction

Team leaders Salah El Mestikawy & Stéphane Jamain and ENP PhD student Diana Yae Sakae just published a study in the journal Molecular Psychiatry in which they combined molecular neuroscience, mouse behavior and human genetic to unravel how glutamate/Acetylcholine cotransmission regulates reward and addiction.

Cholinergic interneurons from the nucleus accumbens express the atypical vesicular glutamate transporter (VGLUT3) in addiction to the vesicular acetylcholine transporter (VAChT). Hence unlike the vast majority of neurons this small population of neurons communicates with 2 transmitters: acetylcholine (Ach) and glutamate (glut). This neuronal bilingualism has important consequences on reward behaviour. Following the disruption of the glutamatergic release from these interneurons VGLUT3-KO mice display a dramatic increase of cocaine self-administration and tendency to relapse. Moreover, human with severe forms of addiction displayed 10 times more mutations on the gene that encodes for VGLUT3 than controls. This study unravels new molecular mechanism underlying addiction and suggests that VGLUT3 is a vulnerability marker of addiction.

Check out the article:

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens, Diana Yae Sakae, Fabio Marti, Salvatore Lecca, Florence Vorspan, Elena Martín-García, Lydie Jacqueline Morel, Annabelle Henrion, Javier Gutiérrez-Cuesta, Antoine Besnard, Nicolas Heck, Etienne Herzog, Susanne Bolte, Vania F. Prado, Marco A.M. Prado, Frank Bellivier, Chin B. Eap, Séverine Crettol, Peter Vanhoutte, Jocelyne Caboche, Alain Gratton, Luc Moquin, Bruno Giros, Rafael Maldonado, Stéphanie Daumas, Manuel Mameli, Stéphane Jamain, Salah El Mestikawy. Molecular Psychiatry, 4 August 2015.

DOI 10.1038/MP.2015.104.

Keywords: addiction, nucleus accumbens, cholinergic interneurons, VGLUT3.

Figure 1 In the nucleus accumbens VGLUT3 is expressed in cholinergic and 5-HT terminals. (a) 3D reconstruction of VGLUT3-positive terminals (red) and 5HT fibers (green). (b) Immunofluorescence of VGLUT3 in red (b1), VAChT in green (b2) and 5HT in blue (b3) in the shell of the NAc. (c)

Figure 2 Dual regulation of dopamine DA efflux by ACh and glutamate released by cholinergic interneurons (TANS) in the nucleus accumbens NAc. TANs express VAChT and VGLUT3 and therefore co-release ACh and glutamate. These 2 co-transmitters exert opposing effects on DA release. In WT mice, (a) DA efflux is stimulated by ACh (through nAChRs) and inhibited by VGLUT3-dependent glutamate (through mGLURs most likely located on DA terminals). In VGLUT3–/– mice (b), the mGLUR-driven inhibition is lost and therefore DA efflux is markedly enhanced. Consequently the DRD1 signaling cascade is over-activated, and dendritic spine density (without modification of the number of excitatory terminals) and cortico-striatal glutamatergic activity are increased, leading to augmented sensitivity to the rewarding properties of cocaine.

Figure 3 Analysis of VGLUT3 (gene SLC17A8) allelic variations and geographical distribution in humans. (a) Average nucleotide diversity for synonymous and non-synonymous substitutions in cohorts of French addicts, Swiss addicts or subjects from the 1000 Genomes (1KG) Project. Average nucleotide diversities for synonymous and non-synonymous substitutions have been calculated per synonymous and non-synonymous site, respectively. (b) Geographical and ethnic distribution of the I8 allele (rs45610843). The super population codes are defined according to the 1KG Project. Abbreviations: AFR, African; AMR, Ad Mixed American; ASN; Asian; EUR, European. Error bars in (a) indicate standard error of the mean. * p<0.05.