Garcia-Castaneda, B. I. | bioRxiv Science

bioRxiv2026

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.

neuroscience↗

bioRxiv2025

Estrous cycle stage gates the effect of stress on reward learning

Stress produces transient physiological responses that lead to long-lasting changes in cue-driven behavior. In particular, a single exposure to stress facilitates reward learning in male rats. Since stress can produce distinct behavioral phenotypes between males and females, it is critical to additionally determine how stress impacts reward learning in females. To address this, female rats were exposed to restraint stress immediately prior to training on an appetitive Pavlovian conditioning task with food rewards. Females were categorized based on their estrous cycle stage on the first day of Pavlovian conditioning. A single exposure to stress enhanced conditioned responding in non-estrus females but suppressed conditioned responding in estrus females. Therefore, a single stress experience produced opposing effects on cue-driven behavior depending upon the estrous cycle stage. In contrast, both estrus and non-estrus rats exposed to repeated prior stress exhibited an increase in conditioned responding relative to animals that underwent a single stress exposure. We further examined if the distal stress experience subsequently impacted extinction and the ability to learn a new cue-reward association. Prior stress did not affect extinction, though estrus and non-estrus rats exposed to repeated prior stress exhibited higher levels of conditioned responding to the novel cue-reward pairing. Taken together, our data demonstrate that the influence of stress on reward learning is impacted acutely by the estrous cycle as well as by ones prior history with stress.

neuroscience↗