The cerebral type 1 cannabinoid receptor as modulator in dopaminergic transmission disorders: addiction and psychosis.

Alcohol addiction is the most common complex psychiatric disorders affecting society. However, the exact signaling pathways and mechanisms underlying the development of alcohol addiction and the relapse propensity are still unclear. Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme highly enriched in striatal medium spiny neurons, where it regulates intracellular signaling processes including dopaminergic transmission. PDE10A is implicated in several psychiatric disorders such as movement disorders, schizophrenia and drug addiction. Involvement of the PDE10A in the effects of alcohol on the brain has only recently been supported by animal studies. Whether PDE10A levels are altered in alcohol-related behaviour in humans is still unknown. In vivo imaging has been made possible very recently by the development of a new PDE10A PET radioligand [18F]JNJ42259152. This radioligand, developed and validated by us and Janssen Pharmaceutics, will combined with the dopamine D2/3 receptor radioligand [18F]fallypride. This allows us to investigate the role of PDE10A and its interaction with dopamine signaling across the different stages of alcohol dependence, both in humans and animal models. This will be combined with functional magnetic resonance imaging (fMRI), behavioral correlates and advanced mathematical modeling tools, in order to identify specific prognostic markers for alcohol relapse risks, and proof-of-principle for potential treatments for alcohol addiction.