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bioRxiv · 10.1101/2022.08.10.503451

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

Serra, V.·Traccis, F.·Aroni, S.·Bortolato, M.·Melis, M.
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Abstract

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; MAOANeo) 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 MAOANeoES 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.

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Serra, V., Traccis, F., Aroni, S., Bortolato, M., Melis, M.. 2022-08-13. Endocannabinoid-dependent persistent decrease of GABAergic transmission on dopaminergic neurons underlies gene-environment interaction-induced susceptibility to cocaine sensitization. https://doi.org/10.1101/2022.08.10.503451

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