Molecular Mechanisms of Antidepressant Action
Introduction
The molecular mechanisms of antidepressant action are complicated because cause (e.g. blocking reuptake) and effect (antidepressant) should be relatively immediate (hours to days) if levels of neurotransmitters were directly related to mood. The typical, longer time course (weeks to months) suggests that secondary mechanisms are critical for the behavioral effect. Elucidating the intermediate, secondary mechanisms is a major focus of basic research with antidepressant compounds.
Approaches to Identify Secondary Targets of Antidepressants
A functional approach utilizes mouse models to test the behavioral effect of either overexpressing (transgenic) or deleting (knockout) a single gene. Then, wild-type (normal) mice are subjected to chronic antidepressant treatment to test whether the same gene is similarly regulated (up-regulated as in overexpression model or down-regulated as in knockout model). A successful, well-designed example of this strategy involved mice that either overexpress or lack p11 (1), a protein that is involved in moving receptors to the surface of cells. (An initial series of experiments identified p11 as a protein that interacts with the serotonin 5-HT1B receptor). Importantly, their results from chronic treatment of wild-type mice with the tricyclic antidepressant imipramine were consistent with their data from genetic models. Although this approach has the potential for great discoveries, the rationale for testing the function of a particular gene must be solid because research studies that involve generating mouse genetic models typically take years to complete.
A genomic approach to identify genes that are influenced by chronic antidepressant treatment has the potential to be very powerful because thousands of genes can be examined. The assay entails comparing the RNA from brains of drug-treated versus saline-treated rodents to identify genes based on expression levels. This approach assumes that secondary mechanisms of antidepressant action require changes in the levels of particular protein. Additional caveats to this approach include an incomplete representation of a rodent genome (all possible genes) and expression levels, meaning that an increased (or decreased) amount of RNA in one small brain region may not be detected in RNA taken from a whole brain. One way of increasing the sensitivity of this assay is to analyze smaller regions of the brain. The most difficult and time-consuming tasks include deciding which genes to study and testing the function of selected genes/gene products. Nonetheless, the initial steps of this approach have successfully identified numerous genes that are influenced by chronic treatment of antidepressants, for example imipramine and citalopram (2). The task of elucidating which genes/gene products are directly involved in mechanism of antidepressant action has begun.
Now What?
The provocative finding in mice that new neurons are required for the antidepressant-like effects of fluoxetine, imipramine, and desipramine may explain the time course of antidepressant action (3). However, as with all good science, it also raises many questions. One important question is why are new neurons needed for the antidepressant effects? Understanding the function of these new neurons will be difficult, but the results may uncover new antidepressant targets and/or shed some light on mechanisms of depression. The answers are only as good as the questions that are being asked.
References
(1) Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P (2006). Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311:77-80.
(2) Palotas M, Palotas A, Puskas LG, Kitajka K, Pakaski M, Janka Z, Molnar J, Penke B, Kalman J (2004). Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram. International Journal of Neuropsychopharmacology 7:401-13.
(3) Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805-9.
Related topics:
Antidepressants
Pharmacology of SSRI compounds