Pathway-specific regulation of amphetamine-induced conditioned place preference by chemogenetic modulation of basolateral amygdala projections to prelimbic cortex and nucleus accumbens subregions

Individuals with substance use disorders develop maladaptive associative memories, linking environmental contexts with drug experiences. The basolateral amygdala (BLA), prelimbic cortex (PrL), and nucleus accumbens (NAc) are central components of the neural circuitry underlying these associations. However, it remains unclear how specific BLA outputs differentially regulate the expression of contextual drug memories. Using designer receptors exclusively activated by designer drugs, we selectively modulated neuronal activity with deschloroclozapine as the activating agent during the expression of amphetamine-induced conditioned place preference (CPP) in the BLA pathways to the PrL, NAc core, and NAc shell. Our findings revealed a dissociation between these pathways: the BLA-to-PrL circuit exerted bidirectional control over CPP expression, with inhibition significantly enhancing and activation attenuating drug-context associations. In contrast, BLA-to-NAc core manipulations selectively modulated locomotor aspects of conditioned responses without affecting place preference, while BLA-to-NAc shell manipulations produced no significant effects on CPP expression. These results demonstrate that the BLA has a distinctive pathway-specific roles in the expression of contextual drug memory.