Ventral tegmental area astrocytes regulate drug-cue associations and drug intake

Cocaine use disorder remains a critical public health concern with limited treatment options. Astrocytes are increasingly recognized as active regulators of neurotransmission and are emerging as important contributors to addiction neurobiology. Here, we examined how chemogenetic activation of astrocytic Gq signaling within the ventral tegmental area (VTA) influences cocaine-associated behaviors in drug-naive and cocaine-experienced rats. Using a subthreshold dose of cocaine in a conditioned place preference (CPP) paradigm, we found that VTA astrocyte Gq activation facilitated the acquisition of cocaine CPP in drug-naive rats but suppressed the development of cocaine CPP in cocaine-experienced rats. Additionally, chemogenetic activation of VTA astrocyte Gq signaling suppressed voluntary cocaine intake in a self-administration paradigm. Together, these findings demonstrate that VTA astrocyte Gq signaling shapes cocaine-associated behaviors in a drug history-dependent manner, highlighting VTA astrocytes as a potential therapeutic target in cocaine use disorder.