Serotonin 2C receptor antagonist improves fear discrimination and subsequent safety signal recall

• Published in: Progress in neuro-psychopharmacology & biological psychiatry 2016-02, Vol.65, p.78-84
• Main Authors: Foilb, Allison R., Christianson, John P.
• Format: Article
• Language: English
• Subjects: 5-HT2C; Aminopyridines - pharmacology; Animals; Anxiety; Conditioned inhibition; Conditioning, Psychological - drug effects; Conditioning, Psychological - physiology; Discrimination, Psychological - drug effects; Discrimination, Psychological - physiology; Electroshock; Fear; Fear - drug effects; Fear - physiology; Freezing Reaction, Cataleptic - drug effects; Freezing Reaction, Cataleptic - physiology; Indoles - pharmacology; Inhibition, Psychological; Male; Mental Recall - drug effects; Mental Recall - physiology; Rat; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C - metabolism; Serotonin 5-HT2 Receptor Antagonists - pharmacology; Stress
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2015.08.017

The capacity to discriminate between safety and danger is fundamental for survival, but is disrupted in individuals with posttraumatic stress disorder (PTSD). Acute stressors cause a release of serotonin (5-HT) in the forebrain, which is one mechanism for enhanced fear and anxiety; these effects are mediated by the 5-HT2Creceptor. Using a fear discrimination paradigm where a danger signal conditioned stimulus (CS+) co-terminates with a mild footshock and a safety signal (CS−) indicates the absence of shock, we demonstrate that danger/safety discrimination and fear inhibition develop over the course of 4 daily conditioning sessions. Systemic administration of the 5-HT2Creceptor antagonist SB 242084 (0.25 or 1.0mg/kg) prior to conditioning reduced behavioral freezing during conditioning, and improved learning and subsequent inhibition of fear by the safety signal. Discrimination was apparent in the first recall test, and discrimination during training was evident after 3days of conditioning versus 5days in the vehicle treated controls. These results suggest a novel therapeutic use for 5-HT2Creceptor antagonists to improve learning under stressful circumstances. Potential anatomical loci for 5-HT2Creceptor modulation of fear discrimination learning and cognitive performance enhancement are discussed. John P. Christianson and Allison R. Foilb, the authors, verify that animal research was carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) and all procedures involving animals were reviewed and approved by the Boston College Animal Care and Use Committee. All efforts were made to limit the number of animals used and their suffering. •Stress enhances fear learning by a 5-HT2C receptor dependent mechanism.•Stress may interfere with danger versus safety discrimination conditioning and recall of learned safety cues.•The 5-HT2C receptor antagonist SB 242084 reduced freezing during conditioning, accelerated discrimination and conditioned inhibition.•5-HT2C antagonists may facilitate learning about safety cues, a desirable therapeutic effect for fear-related psychiatric diseases.