Adiponectin receptor 1-mediated basolateral amygdala-prelimbic cortex circuit regulates methamphetamine-associated memory.

The association between drug-induced rewards and environmental cues represents a promising strategy to address addiction. However, the neural networks and molecular mechanisms orchestrating methamphetamine (MA)-associated memories remain incompletely characterized. In this study, we demonstrated that AdipoRon (AR), a specific adiponectin receptor (AdipoR) agonist, inhibits the formation of MA-induced conditioned place preference (CPP) in MA-conditioned mice, accompanied by suppression of basolateral amygdala (BLA) CaMKIIα neuron activity. Furthermore, we identified an association between the excitatory circuit from the BLA to the prelimbic cortex (PrL) and the integration of MA-induced rewards with environmental cues. We also determined that the phosphorylated AMPK (p-AMPK)/Cav1.3 signaling pathway mediates the modulatory effects of AdipoR1 in PrL-projecting BLA CaMKIIα neurons on the formation of MA reward memories, a process influenced by physical exercise. These findings highlight the critical function of AdipoR1 in the BLA^CaMKIIα→PrL^CaMKIIα circuit in regulating MA-related memory formation, suggesting a potential target for managing MA use disorders.