The non-competitive NMDA receptor antagonist MK-801 induces a complex pattern of behavioral modification in mice with respect to both the time course and the dose-response relationship of behavioral changes. The results of this study provide a foundation and frame of reference for the growing interest in studying MK-801-induced behavior in mice.

To characterize MK-801’s effect on social behavior in mice, we examined adult male ICR mice for interaction with companion mice (juvenile male). Test mice were injected with either saline or MK-801 (0.1 mg/kg), and were tested 30 min later for their social behavior during a 5-min session. A second encounter took place 30 min later, with either a familiar companion mouse (the same as in the initial encounter) or a novel mouse. In saline controls, second encounter with a familiar companion mouse showed reduced social investigative behaviors (anogenital sniffing and staying together), indicating habituation toward a familiar mouse. Second encounter with a novel companion mouse did not show habituation in social investigative behaviors. Pretreatment with MK-801 reduced anogenital sniffing during the first encounter. At the second encounter, these mice displayed non-discriminative habituation of social investigative behaviors, with reduced anogenital sniffing and staying together, regardless of whether the companion mouse was a familiar or a novel one. These results indicate that MK-801 affected exploratory activities of mice, resulting in both reduced social investigative behaviors during first encounter with a companion mouse, and diminished discriminative capacities for a familiar vs. a novel companion mouse during subsequent encounter.

Gut microbiota plays an important role in metabolic homeostasis. Previous studies demonstrated that ginsenoside Rb1 might improve obesity-induced metabolic disorders through regulating glucose and lipid metabolism in the liver and adipose tissues. Due to low bioavailability and enrichment in the intestinal tract of Rb1, we hypothesized that modulation of the gut microbiota might account for its pharmacological effects as well. Here, we show that oral administration of Rb1 significantly decreased serum LDL-c, TG, insulin, and insulin resistance index (HOMA-IR) in mice with a high-fat diet (HFD). Dynamic profiling of the gut microbiota showed that this metabolic improvement was accompanied by restoring of relative abundance of some key bacterial genera. In addition, the free fatty acids profiles in feces were significantly different between the HFD-fed mice with or without Rb1. The content of eight long-chain fatty acids (LCFAs) was significantly increased in mice with Rb1, which was positively correlated with the increase of Akkermansia and Parasuttereller, and negatively correlated with the decrease of Oscillibacter and Intestinimonas. Among these eight increased LCFAs, eicosapentaenoic acid (EPA), octadecenoic acids, and myristic acid were positively correlated with metabolic improvement. Furthermore, the colonic expression of the free fatty acid receptors 4 (Ffar4) gene was significantly upregulated after Rb1 treatment, in response to a notable increase of LCFA in feces. These findings suggested that Rb1 likely modulated the gut microbiota and intestinal free fatty acids profiles, which should be beneficial for the improvement of metabolic disorders in HFD-fed mice. This study provides a novel mechanism of Rb1 for the treatment of metabolic disorders induced by obesity, which may provide a therapeutic avenue for the development of new nutraceutical-based remedies for treating metabolic diseases, such as hyperlipidemia, insulin resistance, and type 2 diabetes.

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