Biomolecular correlates of incubated sucrose-seeking within ventromedial prefrontal cortex are sex- and subregion-selective

The similar temporal profile of incubated food- vs. drug-craving has led to the hypothesis that these behavioral phenomena may involve common, time-dependent, biochemical adaptations within neural circuits governing motivated behavior. Previously, we reported that the mTOR inhibitor Everolimus dose-dependently blocks incubated cocaine-seeking and reverses incubation-related changes in mTOR activation in the prelimbic (PL) subregion of the prefrontal cortex (PFC). Herein, we examined the biomolecular correlates of incubated sucrose-craving within these PFC subregions. Female and male rats were trained to lever-press for 45 mg banana-flavored sucrose pellets, paired with a light + tone compound stimulus during daily 6-h sessions over 10 consecutive days. One or 30 days following the last operant-conditioning session, cue-reinforced responding was assessed. Rats of both sexes exhibited comparable incubated sucrose-craving, yet the majority of incubation-related protein changes were sex-specific. In males, incubated craving was associated with increased indices of Akt/mTOR activation in the IL, and increased mGlu5 dimer expression within both subregions, while females exhibited reduced indices of Akt and PKCε activation, as well as, mGlu5 monomer levels in the PL only. Systemic pretreatment with Everolimus (1.0 mg/kg) produced a modest effect on sucrose cue-reinforced responding that was sufficient to block the incubated response. Taken together, our immunoblotting and behavioral pharmacological data to date argue that different biomolecular mechanisms operate with the IL and PL to drive incubated cocaine- versus sucrose-craving, with mTOR playing a lesser role in the manifestation of incubated sucrose-craving.