eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2025-09-30 18 3 2394 2406 10.13005/bpj/3264 67803 article Ibrahim Abbas Atiyah 1 Seree Niyomdecha 1 Dania Cheaha 1 Department of Biology, Division of Biological Science, Faculty of Science, Prince of Songkla University (PSU), Hatyai, Songkhla, Thailand Major depressive disorder is associated with disrupted limbic network dynamics and impaired behavioral flexibility. While selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are commonly used to treat depression, the acute neural circuit alteration underlying their therapeutic effects remains unclear. The purpose of this research was to examine the effects of acute fluoxetine administration (20 mg/kg) on cross-frequency interactions and local field potential (LFP) activity in the dorsal hippocampus (dHIP) and nucleus accumbens (NAc) during stress-induced behavioral despair. LFPs from the NAc and dHIP were simultaneously recorded, and depressive-like behavior was evaluated in mice using the tail suspension test (TST). The effects of fluoxetine on changes in brain oscillations and circuit synchronization were assessed using power spectral density (PSD) and phase–amplitude coupling (PAC) studies. Results showed fluoxetine significantly reduced immobility during the TST, indicative of rapid antidepressant-like effects. In the NAc, fluoxetine enhanced delta, alpha, beta, and both low and high gamma power, while in the dHIP, it increased gamma power and suppressed delta, theta, and alpha activity. PAC analysis revealed changes of delta/theta–gamma coupling in both regions, with a selective decrease in theta–low gamma coupling in the dHIP. These electrophysiological changes corresponded with improved behavioral engagement and consistent with enhanced monoaminergic modulation and circuit-level plasticity. In conclusion, acute fluoxetine induces rapid reorganization of limbic oscillatory dynamics, characterized by increased gamma activity and enhanced cross-frequency coupling. These findings provide evidence for gamma-band oscillations and PAC as candidate biomarkers of early antidepressant response and support the view that fluoxetine's therapeutic effects involve fast, network-level reconfiguration of mood-relevant circuits. https://biomedpharmajournal.org/vol18no3/acute-fluoxetine-induces-rapid-reorganization-of-limbic-oscillatory-dynamics-gamma-oscillations-and-cross-frequency-coupling-as-correlates-of-antidepressant-like-behavior/ Depression Dorsal Hippocampus Local Field Potential Nucleus Accumbens Phase-Amplitude Coupling Tail Suspension Test