Efficacy of Fluoxetine and (R,S) Ketamine in Attenuating Conditioned Fear Behaviors in Male Mice

Megan Wells; Jan Hoffmann; Autumn Stage; Isabella Enger; Jayme Pomper; Lily Briggs; Amber LaCrosse

doi:10.1124/jpet.124.002252

**Efficacy of Fluoxetine and (R,S) Ketamine in Attenuating Conditioned Fear Behaviors in Male Mice**

J Pharmacol Exp Ther. 2024 Sep 20:JPET-AR-2024-002252. doi: 10.1124/jpet.124.002252. Online ahead of print.

Authors

Megan Wells¹, Jan Hoffmann¹, Autumn Stage¹, Isabella Enger², Jayme Pomper¹, Lily Briggs¹, Amber LaCrosse³

Affiliations

¹ Psychology, Northern Michigan University, United States.
² Biology, Northern Michigan University, United States.
³ Psychology, Northern Michigan University, United States alacross@nmu.edu.

PMID: 39304349
DOI: 10.1124/jpet.124.002252

Abstract

Post-traumatic stress disorder (PTSD) is caused by exposure to a traumatic or stressful event. Symptoms related to this disorder include persistent re-experiencing of memories and fear generalization. Current pharmacological treatments for PTSD are insufficient, with fewer than 30% of patients reporting symptom remission. This study aims to determine the efficacy of acute (R,S) ketamine and chronic fluoxetine (FLX) in reducing fear memory and fear generalization. In rodents, fear conditioning (FC) is commonly used in the literature to induce behaviors related to symptoms of PTSD, and the open field test (OFT) can assess anxiety and fear generalization behaviors during the exploration of a novel environment. In this study, FC consisted of a white noise cue stimulus and four inescapable foot shocks. Treatments began 4 hours after FC. Fear and anxiety behaviors were recorded during re-exposure to the FC stimuli at 24 hours and 2 weeks. The OFT was conducted one day before the last FC re-exposure. Results support the combined use of acute ketamine and chronic FLX as a treatment for reducing behaviors indicative of fear memory during re-exposure at 2 weeks, but not behaviors indicative of anxiety and fear generalization in the OFT. FLX alone was most effective in reducing behaviors related to fear generalization. This study contributes to the existing literature on pharmacological treatment for fear and anxiety behaviors relating to fear memory and fear generalization. Continued research is necessary to replicate results, optimize treatment protocols, and investigate the molecular adaptations to trauma and treatment. Significance Statement Up to 6% of people in the United States will develop PTSD within their lifetime, and less than half of those individuals will find relief from their symptoms given the current therapeutic options. This study offers preliminary support for the efficacy of ketamine and FLX in reducing PTSD-like behaviors induced by fear-conditioning in mice. Compared to current standard treatments, results indicate the potential for a more effective therapeutic option for those with stress-related disorders, such as PTSD.

Keywords: N-methyl-D-aspartate (NMDA); animal models; antidepressants.