Hippocampal Brain-Derived Neurotrophic Factor Expression Following Treatment with Reboxetine, Citalopram, and Physical Exercise

Abstract

The antidepressants, reboxetine and citalopram, were used in conjunction with voluntary physical exercise (wheel running) in order to assess the contribution of noradrenergic and serotonergic activation to enhancements in hippocampal brain-derived neurotrophic factor (BDNF) expression resulting from antidepressant treatment and exercise. Reboxetine (40 mg/kg/day), citalopram (10 mg/kg/day), voluntary physical activity, and the combination of antidepressants with exercise were applied to rats for a range of treatment intervals (2 to 14 days). Hippocampal BDNF transcription levels (full-length BDNF, as well as exons I-IV) were then assessed via in situ hybridization.Reboxetine treatment led to a rapid (evident at 2 days) enhancement in BDNF transcription in several hippocampal regions. This increase was also observed when reboxetine treatment was combined with voluntary physical activity for 2 weeks. Treatment with citalopram led to an increase in BDNF mRNA in only one hippocampal region (CA2) after short-term (2 days) treatment, and when combined with exercise, increased BDNF mRNA in the CA4 and dentate gyrus after 2 weeks. As reported in previous studies, voluntary physical activity enhanced BDNF transcription in several hippocampal areas, both on its own and in combination with antidepressant treatments. Examination of the levels of individual BDNF transcript variants influenced by each of these antidepressants revealed distinct patterns of expression in response to the various treatments, and showed that exercise-plus-antidepressant produced significant changes where antidepressant alone failed. Overall, treatment with the norephinephrine-selective antidepressant, reboxetine, in combination with exercise, led to both rapid and sustained increases in hippocampal BDNF mRNA expression. The serotonergic agent, citalopram, appeared to require longer treatment intervals in order to influence BDNF expression positively.

Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine

“…These include BDNF whose transcription is upregulated by both ECT and SD as previously reported, 13,21,[109][110][111] although unlike other studies 13,112 both microarray and ISH analysis demonstrated that BDNF transcription is not affected by FLX. Similarly, NTRK2 upregulation also confirm earlier reports that neutropin signaling is activated by antidepressant treatments.…”

Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Dysregulation of the HPA Axis and Increases Hippocampal BDNF Protein Levels: Implications for Stress-Related Psychiatric Disorders

“…Intracerebral ventricular or intrahippocampal administration of BDNF has been shown to have an antidepressant-like effect in various animal tests of antidepressant activity (Siuciak et al, 1997;Shirayama et al, 2002;Hoshaw et al, 2005). Furthermore, antidepressant medications have been shown to increase BDNF levels in the hippocampus (Nibuya et al, 1995;De Foubert et al, 2004;Russo-Neustadt et al, 2004; but see Altar et al, 2003;Coppell et al, 2003;Jacobsen and Mork, 2004). Further evidence for a role of BDNF in antidepressant action comes from studies using genetically modified mice with impaired levels of BDNF or its receptor TRK-B, which are resistant to the behavioral effects of antidepressants (Saarelainen et al, 2003).…”

Is it time to reassess the BDNF hypothesis of depression?

“…In addition, antidepressant strategies which do not directly target the monoamine system, such as electroconvulsive shock therapy, transcranial magnetic stimulation, exercise and the novel a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators and N-methyl-D-aspartic acid (NMDA) antagonists, also increase mRNA or protein BDNF levels in the rat brain. 21,[41][42][43][44][45][46][47][48][49] Although the mechanisms involved in BDNF upregulation remain unknown, SSRI and NARI antidepressants have been reported to increase hippocampal levels of cyclic AMP response binding protein (CREB) in the rat, a nuclear transcription factor known to regulate BDNF expression. 32 …”