Enhanced Sensitivity of the MRL/MpJ Mouse to the Neuroplastic and Behavioral Effects of Chronic Antidepressant Treatments

Abstract

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. Because of uncertainty over the effects of chronic antidepressant treatments in mice, these experiments compared the regulation of neurogenesis, mobilization of neurotrophins, and behavior produced by chronic antidepressant treatments between two inbred mouse strains, MRL/MpJ and C57BL/6J. The MRL/MpJ strain is associated with enhanced wound healing and tissue regeneration, whereas C57BL/6J mice are commonly used for behavioral studies. Proliferation and survival of hippocampal progenitor cells were measured using flow cytometry, a new platform that rapidly quantifies BrdU incorporation. Hippocampal cell proliferation was significantly increased following chronic administration of fluoxetine (5, 10 mg/kg; i.p. b.i.d.) or desipramine (5, 10 mg/kg; i.p. b.i.d.) for 21 days in MRL/MpJ mice, but not in C57BL/6J 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 MRL/MpJ mice were elevated significantly in the frontal cortex, hippocampus, and amygdala following chronic fluoxetine treatment, but increased only in the frontal cortex by chronic desipramine. In contrast, BDNF levels in C57BL/6J mice were decreased in all regions except for the amygdala after chronic fluoxetine, and were decreased in the brain stem after chronic desipramine. Novelty-induced hypophagia was used to examine a behavioral effect produced by chronic antidepressant treatment. MRL/MpJ mice chronically administered fluoxetine or desipramine 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 C57BL/6J 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 MRL/MpJ, but none of these effects were produced in C57BL/6J mice. The greater responsiveness of MRL/MpJ 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.