Endocannabinoid-dependent persistent decrease of GABAergic transmission on dopaminergic neurons underlies gene-environment interaction-induced susceptibility to cocaine sensitization

Vulnerability to develop cocaine use disorder depends upon an unpredictable combination of genetic and non-genetic risk factors. Early life adversity and adolescence are critical non-genetic risk factors, and haplotypes of the monoamine oxidase (MAO) genes are among genetic variations increasing the risk of drug-related problems. However, data on the interactions between inheritable risk factors and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model containing both genetic (low-activity alleles of the MAO A gene; MAOA Neo ) and environmental (i.e., ES) variables displays a long lasting increased sensitivity to repeated in vivo cocaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from MAOA Neo ES mice treated repeatedly with cocaine. Activation of either dopamine D2 or CB1 receptors is required for cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next, in vivo pharmacological enhancement of 2-AG signaling during repeated cocaine exposure occludes its actions both in vivo and ex vivo . This data extends our knowledge of the multifaceted sequelae imposed by this gene by environment interaction in VTA dopamine neurons of male pre-adolescent mice, contributing to our understanding of neural mechanisms of vulnerability for early onset cocaine use disorder.