Pharmacological activation of the lateral orbitofrontal cortex on regulation of learned fear and extinction

•Orbitofrontal cortex (OFC) was activated at three phases of fear extinction (ext).•Pre-Ext and Pre-Test OFC activation disrupted fear expression.•Pre-Ext OFC activation impaired extinction encoding.•OFC activation or not, Post-Ext manipulation interfered extinction consolidation. Obsessive-compulsive disorder (OCD) is usually accompanied with hyperactivity of the orbitofrontal cortex (OFC). OCD patients have anxiety issues, and there is high comorbidity of OCD and post-traumatic stress disorder (PTSD). One of the leading factors of PTSD is the failure of fear extinction. In this study, we examined whether hyperactivity of the OFC interfered with extinction processes. The lateral OFC (lOFC) was pharmacologically activated with N-methyl-d-aspartate (NMDA) in behaving rats during encoding, consolidation, and retrieval, of Pavlovian fear extinction. We found that when we brought the lOFC on-line before extinction training or retrieval test, there was a general initial suppression of fear expression regardless behavioral history, which was followed by development of nonspecific fear response. Moreover, pre-extinction activation of the lOFC impaired the encoding of extinction demonstrated by a general up-shift of fear levels during retrieval test compared to controls. We also found that regardless of whether the lOFC was activated or not, immediate post-extinction manipulation interfered extinction consolidation in general. To conclude, activation of the lOFC altered expression of learned fear and negatively impaired extinction outcome. Our results provided a new angle to study the etiology of comorbid OCD and PTSD.