Addiction is a compulsive pattern of drug-seeking/drug-taking behavior with recurring episodes of abstinence and relapse, and a loss of control despite negative consequences. Addiction is primarily a disease of the brain reward system. In order to improve treatment and prevention strategies for addiction disorders, a substantially improved understanding of reward circuits critical for addiction processes is required. Given their regulatory properties in the basal ganglia, cholinergic interneurons (TANs) from the nucleus accumbens (NAc) have been the focus of many studies. However, their role remains largely elusive. Ablation of TANs markedly increases rewarding properties of cocaine. Recently, a mouse line with selective elimination of the vesicular acetylcholine transporter (VAChT) from TANs was developed. Because VAChT is essential for ACh vesicular storage, these mutants no longer release ACh in the NAc. Surprisingly, this mouse line showed minimal alteration in behavioural responses to cocaine. Thus ACh does not seem essential to regulate reward. Furthermore, these results suggest that TANs use another neurotransmitter to signal. Indeed, we established 8 years ago that TANs express an atypical vesicular glutamate transporter (named VGLUT3) in their terminals. Consequently, TANs store and release two classical neurotransmitters: ACh and glutamate (Glu). The respective functions of Glu and ACh released by TANs and their role in striatum-related functions as well as pathologies remain to be understood. Additionally, we observed that mice deficient for the VGLUT3 (VGLUT3-KO) are more responsive to cocaine than wild-type littermates, phenocopying mice with ablation of TANs. Based on these recent results, the COCACE proposal is built around 3 major uestions, all focussing around the role of VGLUT3 and TANs in reward circuitries of relevance to ddiction: i) Do TANs modulate reward behaviors through glutamate release and not through ACh? ii) oes alteration of VGLUT3 increase vulnerability to addictions in mouse models as well as in humans? iii) Do addicted humans have a particular psychiatric profile? To address these questions, we will use ultidisciplinary approach to bridge the gap between VGLUT3, reward behaviors and addiction. We will define the role of VGLUT3 in reward circuits using multiple mouse models (i.e. constitutive or conditional knockout (KO) mice, as well as knock-down mice). In addition, we already screened a sample of patients with severe addiction to cocaine and identified several mutations in SLC17A8, the gene encoding VGLUT3. We now propose to characterize these mutated alleles by anatomical, biochemical and electrophysiological methods. Furthermore, patients carrying VGLUT3 mutation will be clinically characterized (lifetime addictive history, lifetime Axis I psychiatric disorders including ADHD, anxiety disorders, personality traits (impulsivity, anxiety) and level of drug craving). Finally, we will extend our mutation screening to additional subjects with addiction as well as to other genes encoding the VGLUT family. This combination of experimental approaches is expected to increase our understanding of molecular mechanisms underlying reward and, on the long range, to identify a genetic vulnerability factor and a novel target for the treatment of addictions.
Electrophisiological approaches, Behavioural methodologies, Glutamate, Gene targeting in the brain, aetiology, addiction, genetic vulnerability, nucleus accumbens, cholinergic interneurons, co-transmission, VGLUT3, acetylcholine, substance use disorders