PREFRONTAL GLUTAMATERGIC CONTROL OF ALCOHOL-RELATED BEHAVIORS IN MALE LONG-EVANS RATS : DREADDS AND CALCIUM IMAGING APPROACHES

Alcohol Use Disorder (AUD) is characterized by a chronic and relapsing course, with loss of control over alcohol intake and compulsive consumption. It is also associated with dysfunctions within the medial prefrontal cortex (mPFC), a key brain region involved in executive control, decision-making, and behavioral inhibition. The mPFC and its subdivisions, predominantly composed of glutamatergic pyramidal neurons, exert top-down regulation over mesocorticolimbic circuits. We used DREADDs to selectively modulate the activity of glutamatergic neurons in the mPFC and its main subdivisions in adult male Long-Evans rats during operant alcohol self-administration. To obtain a convergent functional readout, we also performed in vivo calcium imaging to monitor the activity of mPFC glutamatergic neurons throughout the behavioral sessions. Our results show that chemogenetic activation of the prelimbic (PL) cortex glutamatergic neurons, significantly reduces motivation for alcohol, whereas their inhibition enhances alcohol-directed motivation. Calcium imaging revealed that glutamatergic neuronal activity in the mPFC dynamically tracks alcohol-related actions, with increased activity time-locked to both alcohol seeking and consumption. Together, these findings indicate that the mPFC exerts a critical inhibitory control over the motivational processes driving alcohol use, with distinct contributions of its subdivisions, notably the PL and infralimbic (IL) cortices, to different facets of alcohol-related behavior. These data further support the notion that restoring prefrontal inhibitory control through targeted modulation of mPFC activity may represent a promising therapeutic strategy for AUD.