Pain and reward circuits antagonistically modulate alcohol expectancy to regulate drinking

Expectancy of physical and social pleasure (PSP) promotes excessive drinking despite the potential aversive effects of misuse, suggesting an imbalance in the response to reward and pain in alcohol seeking. Here, we investigated the competing roles of the reward and pain circuits in PSP expectancy and problem drinking in humans. Using fMRI data during resting (n = 180) and during alcohol cue exposure (n = 71), we examined the antagonistic effects of the reward-related medial orbitofrontal cortex (mOFC) and pain-related periaqueductal gray (PAG) connectivities on PSP expectancy and drinking severity. The two regions' connectivity maps and strengths were characterized to assess their shared substrates and net relationship with PSP expectancy. We evaluated mediation and path models to further delineate how mOFC and PAG connectivities interacted through the shared substrates to differentially impact expectancy and alcohol use. During resting, whole-brain regressions showed mOFC connectivity in positive and PAG connectivity in negative association with PSP scores, with convergence in the precentral gyrus (PrCG). Notably, greater PAG-PrCG relative to mOFC-PrCG connectivity strength predicted lower PSP expectancy. During the alcohol cue exposure task, the net strength of the PAG vs. mOFC cue-elicited connectivity with the occipital cortex again negatively predicted PSP expectancy. Finally, mediation and path models revealed that the PAG and mOFC connectivities indirectly and antagonistically modulated problem drinking via their opposing influences on expectancy and craving. Thus, the pain and reward circuits exhibit functional antagonism such that the mOFC connectivity increases expectancy of drinking pleasure whereas the PAG serves to counter that effect.