OPTOGENETIC DISSOCIATION OF CINGULATE AND PRELIMBIC CORTEX FUNCTION IN MORPHINE-INDUCED REWARD AND AVERSION: NEURAL SUBSTRATES UNDERLYING THE PARADOXICAL EFFECT HYPOTHESIS

Until now, no study has directly examined whether the cingulate cortex 1 (Cg1) and prelimbic cortex (PrL), two major subregions of the medial prefrontal cortex, differentially modulate morphine-induced reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA) through glutamatergic neuronal pathways. The study employed optogenetic approaches to clarify how activation or inhibition of the Cg1 and PrL regulates the paradoxical reward and aversion of morphine. Expression levels of specific neural markers—including c-Fos and BDNF—were quantified in targeted brain regions (Cg1, PrL, IL, NAc, BLA, CeA, CA1, CA3, and DG). Moreover, NMDA and D1 receptors were selectively examined in the basolateral amygdala (BLA). Photostimulation of glutamatergic neurons in the Cg1 using ChR2 suppressed morphine-induced CTA aversion while simultaneously facilitating CPP reward. c-Fos expression was regulated in the BLA and widespread BDNF upregulation across cortical and limbic regions. D1 receptor expression in the BLA was significantly elevated, but NMDA receptor levels did not differ between saline and morphine groups. Photoinhibition of the PrL via eNpHR3.0 enhanced both CTA aversion and CPP reward induced by morphine. c-Fos expression was regulated in both the Cg1 and PrL, widespread BDNF upregulation, nonsignificant changes in NMDA receptor levels, and increased D1 receptor expression in the BLA.
Altogether, these findings reveal a functional dissociation between the Cg1 and PrL in regulating morphine-induced reward and aversion, supporting a neural basis for the paradoxical effect hypothesis of abused drugs. The data highlight distinct prefrontal–amygdala mechanisms underlying how morphine produces competing motivational states.