Abdominal Ultrasound Stimulation Alleviates Negative Symptoms Through Modulation of Serotonin Signaling and Gut Microbiota in the MK-801 Model of Schizophrenia

Background and Hypothesis Abdominal low-intensity pulsed ultrasound (LIPUS) stimulation has potential as a novel therapeutic strategy against neuroinflammation via inhibition of inflammatory responses in the colon. This study aimed to evaluate whether abdominal LIPUS could alleviate MK-801-induced schizophrenia-like negative symptoms through gut–brain communication. Study Design Rats administered with MK-801 were treated daily for 5 days with either LIPUS or Lactobacillus plantarum PS128, while another group of MK-801-administered rats received no treatment. Following LIPUS or PS128 treatment, rats underwent behavioral testing, western blot analysis, and histological examination. Changes in the gut bacteria composition were examined through 16S rRNA sequencing analysis. Study Results MK-801 administration reduced NMDAR1 and VGAT expression in the medial prefrontal cortex (mPFC) of rats, leading to an imbalance in the excitation/inhibition (E/I) ratio. It also decreased 5-HT1AR and 5-HT2AR density, resulting in reduced concentrations of dopamine and serotonin (5-HT). This induced prepulse inhibition, anhedonia, and social withdrawal behaviors, accompanied by a reduction in gut microbiota diversity. Abdominal LIPUS stimulation effectively lessened the MK-801-induced reduction in gut microbiota diversity, restored NMDAR1, 5-HT1AR, and 5-HT2AR density, enhanced dopaminergic neuron activity, and increased dopamine and 5-HT release in the mPFC, thereby reversing behavioral abnormalities. Conclusions These results suggest that abdominal LIPUS alleviates MK-801-induced schizophrenia-like negative symptoms by modulating serotonin signaling and the gut microbiota.