Establishment of a Mouse Model of Stress–Cocaine Cross-Sensitization to Investigate Rac1 Signaling

Repeated stress exposure potentiates behavioral responses to cocaine through neuroadaptations in the Nucleus Accumbens (NAc). In our laboratory, we previously characterized a cross-sensitization paradigm between repeated restraint stress and cocaine in rats. Here, we aimed to establish and optimize this experimental approach in mice to investigate the molecular and cellular mechanisms underlying this phenomenon. We implemented a protocol involving five days of repeated restraint stress followed by cocaine administration and evaluated locomotor activity as a measure of cocaine sensitization. Following optimization of the experimental conditions, we successfully reproduced cross-sensitization in male mice, whereas this effect was not observed in females. This mouse model expands the experimental approaches available to investigate the mechanisms linking stress to cocaine-induced behavioral sensitization and provides a foundation for further studying the Rho GTPase Rac1 signaling in this context. Previous findings from our laboratory showed that chronic stress induces structural and functional neuroadaptations in the NAc and alters cofilin activity. Given the role of Rac1 in cofilin regulation and actin cytoskeleton dynamics, we hypothesize that stress-induced alterations in Rac1 signaling contribute to NAc dendritic spine remodeling associated with increased vulnerability to cocaine.