Chemogenetic Inactivation of Orbitofrontal Cortex Decreases Cue‐induced Reinstatement of Ethanol and Sucrose Seeking in Male and Female Wistar Rats

Background The orbitofrontal cortex (OFC) encodes internal representations of outcomes and subjective value to facilitate flexible reward seeking. OFC activation is associated with drug seeking in both human subjects and animal models. OFC plays a role in alcohol use, but studies in animal models have produced conflicting results with some showing decreased seeking after OFC inactivation but others showing increased seeking or no changes. In part, this may be due to the different measures of alcohol seeking used (e.g., homecage drinking vs. operant seeking). Methods We characterized the impact of transient inactivation of OFC (primarily lateral and, to a lesser extent, ventral subregions) using inhibitory hM4Di designer receptors exclusively activated by designer drugs (DREADDs). OFC neurons were transiently inhibited during 10% and 20% alcohol (ethanol, EtOH) and sucrose homecage consumption, fixed ratio (FR1) operant self‐administration, and cue‐induced reinstatement of either 10% EtOH or sucrose in male and female rats. Results OFC inactivation did not affect sucrose or EtOH consumption in the homecage, nor did it influence seeking or consumption under FR1 operant conditions. In contrast, OFC inactivation suppressed cued‐induced reinstatement for both EtOH and sucrose in both male and female rats. Conclusions Our results are aligned with previous work indicating a selective suppressive effect of OFC inactivation on reinstatement for alcohol and other drugs of abuse. They extend these findings to demonstrate no effect on homecage consumption or FR1 seeking as well as showing an impact of sucrose reinstatement. These data indicate that OFC plays a uniquely important role when reward seeking is driven by associations between external stimuli and internal representations of reward value, both for natural and drug rewards. They further implicate the OFC as a key structure driving relapse‐associated seeking and potentially contributing to alcohol use disorder and other diseases of compulsive reward seeking. By transiently inactivating neurons in the rat orbitofrontal cortex (OFC) using chemogenetics, Hernandez and colleagues found that OFC disruption decreased reinstatement of alcohol seeking, but had no effect on alcohol drinking or self‐administration. Similar effects were found in males and females, and similar outcomes occurred when sucrose was tested instead of alcohol. Together these findings demonstrate an important role for OFC in alcohol reinstatemen