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.

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

“…In addition, there are no differences in normal anxiety levels in elevated-plus-maze and open-field tests in VGF ϩ/Ϫ mice, but there are deficits in the depression paradigms FST and TST (Hunsberger et al, 2007). Finally, the response to chronic antidepressants in the noveltyinduced hypophagia test has been shown to be associated with neurogenesis at least in some mouse strains (Balu et al, 2009), which is suggestive of an antidepressant-like effect because antidepressants but not anxiolytics have been shown to increase neurogenesis.…”

Epigenetics of the Depressed Brain: Role of Histone Acetylation and Methylation

“…Depressed patients also display decreased levels of the NR2A and NR2B NMDA glutamate receptor subunits as well as a reduction in PSD-95, all of which are crucial for the structural integrity and function of dendritic spines (Gambrill and Barria, 2011). Chronic stress decreases levels of BDNF in the PFC (Fumagalli et al, 2004) and, similar to the hippocampus, levels are increased after treatment with antidepressants (Balu et al, 2009). Interestingly, neuropeptide Y, which antagonizes the actions of corticotrophin-releasing hormone (Giesbrecht et al, 2010;Heilig, 2004), is also decreased in the PFC of depressed patients and suicide victims (Caberlotto and Hurd, 2001;Widdowson et al, 1992).…”

Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice

“…Adult male and female MRL/MpJ mice (The Jackson Laboratory, Bar Harbor, ME) were 7 to 10 weeks old at the beginning of all the studies. MRL/MpJ mice show enhanced regenerative responses to injury, and males show robust increases in neurogenesis after long-term treatment with both fluoxetine and desipramine (Balu et al, 2009a). Mice were group-housed (five to a cage, single sex) in polycarbonate cages and maintained on a 12-h light/dark cycle (lights on at 7:00 AM) in a temperature-(22°C) and humidity-controlled colony.…”