Enhanced sensitivity of the MRLMpJ mouse to the neuroplastic and behavioral effects of chronic antidepressant treatments

Chronic administration of antidepressant drugs produce changes in neuroplasticity and behavior in rodents, effects that may be associated with the slow emergence of clinical therapeutic effects. Owing to the uncertainty over the effects of chronic antidepressant treatments in mice, these experiments compared the regulation of neurogenesis, neurotrophin levels, and behavior produced by chronic antidepressant treatments between two inbred mouse strains, MRLMpJ and C57BL6J. The MRLMpJ strain is associated with enhanced wound healing and tissue regeneration, whereas C57BL6J mice are used commonly for behavioral studies. Proliferation and survival of hippocampal progenitor cells were measured using flow cytometry, a new platform that rapidly quantifies the incorporation of 5-bromo-2-deoxyuridine (BrdU). Hippocampal cell proliferation was increased significantly after chronic administration of fluoxetine (FLX: 5, 10mgkg, intraperitoneal (i.p.), b.i.d.) or desipramine (DMI: 5, 10mgkg, i.p., b.i.d.) for 21 days in MRLMpJ mice, but not in C57BL6J mice. Hippocampal progenitor cells born prior to chronic antidepressant treatments were not affected in either mouse strain. Protein levels of brain-derived neurotrophic factor (BDNF) in MRLMpJ mice were elevated significantly in the frontal cortex, hippocampus, and amygdala after chronic FLX treatment, but increased only in the frontal cortex by chronic DMI. In contrast, BDNF levels in C57BL6J mice were decreased in the hippocampus and increased in the amygdala after chronic FLX, and were decreased in the brain stem after chronic DMI. Novelty-induced hypophagia (NIH) was used to examine a behavioral effect produced by chronic antidepressant treatment. MRLMpJ mice, chronically administered FLX or DMI, had significantly shorter latencies to consume food when exposed to a novel environment than untreated mice, whereas there were no effects on the behavior of C57BL6J mice. In conclusion, robust effects of chronic antidepressant treatments on hippocampal cell proliferation and BDNF levels paralleled the ability of these drugs to produce changes in NIH behavior in MRLMpJ, while none of these effects were produced in C57BL6J mice. The greater responsiveness of MRLMpJ mice may be important for drug discovery, for genetic studies, and for understanding the neural mechanisms underlying the physiological and behavioral effects of chronic antidepressant treatments.