Antidepressants: Neurogenesis vs. Neuroplasticity - Dana Walker

Separately, Santarelli et al.’s 2003 article and Bessa et al.’s 2009 article provide scientifically supported views on the effects of antidepressants on the hippocampus; specifically, how they impact hippocampal neurons to result in behavioral improvements. Santarelli and colleagues propose hippocampal neurogenesis is required for antidepressants to have any effect. They subjected mice to low-dose x-irradiation, effectively blocking 5-HT1A receptors and reducing neurogenesis in the subgranular zone by 85%. These affected mice, when treated with antidepressants, failed to show the same decreased latency to feed as sham mice. These mice also showed smaller improvements following a chronic unpredictable stress paradigm and subsequent fluoxetine treatment. The authors suggested a potential causal relationship between the deletion of the 5-HT1A receptor and failure of antidepressants to improve symptoms, citing their finding that disrupting hippocampal neurogenesis blocked the effects of antidepressant treatment.

Bessa and colleagues, on the other hand, suggest it is neuroplasticity, not neurogenesis, that aid antidepressants in improving mood. They subjected rats to a chronic mild stress procedure, then administered several behavioral tests to assess stress. MAM was administered in a group of rats as a means of reducing neurogenesis by 60% in the dentate gyrus. Behaviorally, stressed rats showed reduced sucrose consumption, an effect that was reversed by antidepressants, even when MAM was administered. Furthermore, chronic stress reduced the density of cells labeled for Ki-67 and BrdU, as well as the volume of the dentate gyrus. Antidepressants reversed these effects. The authors claimed these results simultaneously support the negative effect of chronic mild stress on neurogenesis and the positive effect of antidepressants. They propose while neurogenesis is still a process promoted by antidepressants, neuroplasticity is the critical process occurring in the hippocampus that leads to behavioral changes.

However, I believe directly comparing these two articles against each other is like comparing apples and oranges. It is possible differences in methodology could account for the differences in these authors’ conclusions. For starters, the mechanism with which each study inhibited neurogenesis in the hippocampus was varied. Using a cytostatic agent (MAM) was less effective at reducing neurogenesis than irradiation. Second, the assessments and conditions varied between the two studies and could produce different results. The 2003 study used 5-HT1A knockouts or wildtype mice and subjected them to a chronic unpredictable stress paradigm and food consumption test, evaluated based on grooming latency and state of the fur. The 2009 study focused on stress, using a chronic mild stress protocol alongside the sucrose preference test, forced swimming test, and novelty suppressed feeding.

Based on these differences in methodology, I would recommend controlling for more components of the experimental procedure before attempting to tease apart the roles of neurogenesis and neuroplasticity in the hippocampus. These papers leave the reader questioning if the two different protocols may be responsible for contrasting conclusions.