Role of the CRF / NPY balance within the amygdala and its control over striatal neurophysiology in inter-individual vulnerability to develop compulsive heroin self-administration in the rat – Heraddicstress

Drug addiction is a heavy social and economical burden for modern societies. There is yet no effective treatment or preventive strategy for this complex relapsing brain disorder. Among the individuals exposed to drugs only 15 to 30% make the transition from controlled to compulsive drug use. These drug addicts not only take drugs, they spend great amounts of time foraging for their drugs, lose control over and compulsively take drugs, persisting in taking drugs despite the many adverse consequences of doing so, including compromising their health, family relationships, friendships and work. This negative behavioural picture illustrates how drug addiction is not merely a drug taking disorder, but is defined as a chronic relapsing disorder characterized by loss of control over drug intake and compulsive drug seeking and taking as described by the DSM-IV. Therefore it is important to separate two issues: (i) why people take drugs in the first place and (ii) why some people lose control over drug use and compulsively take drugs. While major advances have been made in the understanding of the psychobiological factors involved in individual vulnerability to cocaine, addiction, our knowledge of the underpinnings of individual vulnerability to switch from controlled to compulsive heroin intake remains very limited. There is however increasing evidence that heroin addiction may be associated with a recruitment of stress-related peptides, especially within the amygdala, a ‘between-systems’ adaptation that we have integrated into our new psychobiological model of addiction, whereby an alteration of the functional balance of the CRF/NPY peptide systems within the basolateral nucleus of the amygdala (BLA) facilitates BLA-striatal functional interactions recruited by heroin to underpin the establishment of the “incentive habit” of drug seeking and taking. We therefore propose to reveal new perspectives in the understanding of opiate addiction by developing a new animal model of addiction-like behaviour for heroin and test the hypothesis that alterations in stress/anxiety-related peptides function within amygdalo-striatal circuitry contribute to an endophenotype of increased individual vulnerability to switch from controlled to compulsive heroin self-administration. This project, which is a development in direct line with our past activity as an INSERM AVENIR team (2009-2012), lies at the core of our activity not only as an independent team within the future Neurosciences Laboratory directed by Mohamed Jaber in Poitiers, but also as part of an INSERM European Associated Laboratory with Professor Barry Everitt’s laboratory in Cambridge. This project is based on a tight and productive collaboration between our two laboratories and will mobilise post-doctoral fellows from Cambridge and Poitiers, including one funded by the ANR. The project has four main objectives organised in an original vertical Strategy distributed over four years: 1. Characterisation of factors of vulnerability to, and cognitive consequences of, addiction-like behaviour for heroin 2. Identification of the role of BLA-striatal interactions in individual vulnerability to heroin addiction 3. Identification of the role of amygdala CRF/NPY functional balance in individual vulnerability to develop compulsive heroin self-administration 4. Identification of the neural and cellular mechanisms whereby amygdala stress-related peptides contribute to increased vulnerability to heroin addiction. Our strategy integrates experimental psychology, neural systems physiology and pharmacology, cellular and synaptic plasticity and molecular biology implemented in successive correlational and causal approaches distributed throughout a longitudinal design encompassing drug-naïve states of vulnerability and addiction-like behaviour. T This project has clear medical and translational implications because it should provide new insights into heroin addiction.