PREGNENOID

The growing demand for both medical and non-medical cannabis worldwide has become a great public health challenge. The increasing potency of cannabis and prevalence of its use in many countries, including in Europe (and in France) constitute a high risk factor for the emergence of cannabis use disorders (CUD), for which efficient treatment is lacking. Elucidating the mechanisms of action involved in cannabis abuse, as well as the beneficial vs. undesirable effects of cannabinoids (CBs) for medicinal use, is a prerequisite for a therapeutic goal. The main psychoactive component of Cannabis sativa plant, ?9-tetrahydrocannabinol (THC) acts mostly via cannabinoid receptors 1 (CB1Rs) in the brain, which are the natural target of the endogenous cannabinoids. Knowing that the effects of CBs and THC can be adjusted by the endogenous negative allosteric modulator pregnenolone (PREG), and by the subcellular localization of CB1Rs, this collaborative project aims at elucidating the cellular mechanism underlying the regulation of CB1-mediated effects by the endogenous PREG. The objectives of the project are to unravel the cellular and molecular basis of the occurrence of the PREG-CB1R regulatory loop involved in the beneficial and adverse effects of CBs, as well as CUD-related behaviors. Our project will use an original methodological design with multi-combined approaches going from molecular and cell biology to behavioral analyses in CB1R genetically modified mice. In particular we will use the newly generated CB1-E134G mice, which lack PREG-CB1R regulation and thus demonstrate increased sensitivity to THC and may represent a vulnerable genotype for the development of CUD. Therefore, this project will contribute to the identification of new therapeutic targets for CUD as well as for the management of safe medication with THC derivatives.