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The full list of Conflicts of interest is given in Appendix S1. Data availabilityThe data that support the findings of this study are available upon reasonable request. Further

Rationale The gut microbiota is increasingly recognized as a potential mediator of psychiatric diseases. Depressed patients have been shown to have a different microbiota composition compared with healthy controls, and several lines of research now aim to restore this dysbiosis. To develop novel treatments, preclinical models may provide novel mechanistic insights. Objective and methods We characterized the gut microbiota of male adult Flinders sensitive line (FSL) rats, an animal model of depression, and their controls, Flinders resistant line (FRL) rats using 16S rRNA amplicon sequencing. Moreover, we performed fecal microbiota transplantation (using saline or pooled FRL/FSL feces) to study if the potential strain-specific differences could be transferred from one strain to the other, and if these differences were reflected in their depressive-like behavior in the forced swim test. Results FSL rats tended to have lower bacterial richness and altered relative abundances of several bacterial phyla, families, and species, including higher Proteobacteria and lower Elusimicrobia and Saccharibacteria . There was a clear separation between FRL and FSL rat strains, but no effect of treatment, i.e., the bacterial composition of FSL rats receiving FRL feces was still more similar to FSL and not FRL rats. Similarly, the transplantation did not reverse behavioral differences in the forced swim test, although FSL feces significantly increased immobility compared with saline. Conclusions Our study showed that the gut microbiota composition of the depressive-like rats markedly differed from their controls, which may be of value for future microbiota-targeted work in this and similar animal models. Electronic supplementary material The online version of this article (10.1007/s00213-018-5094-2) contains supplementary material, which is available to authorized users.

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ScopeProbiotics may influence one‐carbon (C1) metabolism, neurotransmitters, liver function markers, or behavior.Methods and resultsMale adult Flinders Sensitive Line rats (model of depression, FSL; n = 22) received Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (109 or 1010 colony‐forming units per day) or vehicle for 10 weeks. The controls, Flinders Resistant Line rats (FRL, n = 8), only received vehicle. C1‐related metabolites were measured in plasma, urine, and different tissues. Monoamine concentrations were measured in plasma, hippocampus, and prefrontal cortex. Vehicle‐treated FSL rats had higher plasma concentrations of betaine, choline, and dimethylglycine, but lower plasma homocysteine and liver S‐adenosylmethionine (SAM) than FRLs. FSL rats receiving high‐dose probiotics had lower plasma betaine and higher liver SAM compared to vehicle‐treated FSL rats. FSLs had higher concentrations of norepinephrine, dopamine, and serotonin than FRLs across various brain regions. Probiotics decreased plasma dopamine in FSLs in a dose‐dependent manner. There were no detectable changes in liver function markers or behavior.ConclusionsProbiotics reduced the flow of methyl groups via betaine, increased liver SAM, and decreased plasma dopamine and norepinephrine. Since these changes in methylation and catecholamine pathways are known to be involved in several diseases, future investigation of the effect of probiotics is warranted.

Probiotic administration to rodents is typically achieved using oral gavage or water bottles, but both approaches may compromise animal welfare, bacterial viability, dosing accuracy, or ease of administration. Oral gavage dosing may induce stress, especially when given daily over several weeks, and cannot be performed by inexperienced personnel. Delivery in water bottles does not take multiple co-housed animals into account, leading to inaccurate dosing of individual rats. Moreover, slow consumption of the solutions over several hours may lead to variability in bacterial stability, and potential leftovers or clogging of the bottle further threaten the reliability of this method. To date, no method has been described that can provide non-stressful precise dosing of probiotics or prebiotics in individual rats. In accordance with the 3R principles (replace, reduce, refine), we propose syringe-feeding as a refinement method for simple yet accurate administration of probiotics. Animals hereby voluntarily consume the solution directly from a syringe held into their home cage, thereby enabling controlled dosing of individual animals. This method requires a short training phase of approximately 3 days, but is very fast thereafter, only taking seconds per rat. Since studies using probiotics are usually long-term experiments, we consider syringe-feeding the most appropriate probiotic delivery mode available to date.

N-methyl-D-aspartate receptor (NMDA-R) antagonists and nitric oxide inhibitors have shown promising efficacy in depression but commonly induce adverse events. To circumvent these, a more indirect disruption of the nitric oxide synthase/postsynaptic density protein 95 kDa complex at the NMDA-R has been proposed. This disruption can be achieved using small molecule inhibitors such as ZL006, which has attracted attention as ischemic stroke therapy in rodents and has been proposed as a potential novel treatment for depression. Based on this, our aim was to translate these findings to animal models of depression to elucidate antidepressant-like properties in more detail. In the present study, we administered ZL006 to two established animal models of depression and control rodents. Following treatment, we measured locomotion in the Open Field and depressive-like behavior in the Forced Swim Test and Tail Suspension Test. Our experimental designs included the use of different species (rats, mice), strains (Flinders Sensitive Line rats, Flinders Resistant Line rats, Wistar Kyoto rats, Wistar Hanover rats, Sprague Dawley rats, B6NTac mice), routes of administration (intraperitoneal, intracerebroventricular), times of administration (single injection, repeated injections), treatment regimens (acute, sustained), and doses (5, 10, 15, 50 mg/kg). ZL006 did not affect behavior in any of the described settings. On a molecular level, ZL006 significantly reduced total nitrate/nitrite concentrations in the cerebellum, supporting that it is capable of reducing nitric oxide metabolites in the brain. Future studies using different experimental parameters are needed to further investigate the behavioral profile of ZL006.

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