Behavioral and neuroendocrine assays for studying epilepsy-associated depression.

To the Editors: In their review, Brooks-Kayal et al. (2013) provided guidelines for using certain assays to study epilepsy-associated depression in the laboratory. These guidelines should be further refined so as to improve construct validity of models in question, throughput of preclinical trials, and the reliability of the findings. 1 The authors propose the Porsolt test to study the inability of animals to cope with a stressful situation. The Porsolt test, which has been proposed for the use in inherently normal animals, consists of two steps. Step 1 is a 15-min swimming session purposed to induce depression; step 2 is the test proper, where animal’s immobility is measured during the 5-min swimming trial. Models of major depression that involve animals with an inherently depressive phenotype, do not utilize the Porsolt test. Indeed, if the animal is already depressed, the first (i.e., depressogenic) swimming session is no longer required. Instead, a single 5min trial is used, whereby depressed animals exhibitprolonged immobility visa-vis normal counterparts (Overstreet & Wegener, 2013). Epileptic rats show consistently increased immobility in the single-session test, that is they are depressed by the virtue of having epilepsy (Mazarati et al., 2008). Hence, the Porsolt test becomes unnecessary. The single-session test can be successfully applied for screening of effective therapies (Pineda et al., 2012). Not only would replacement of the Porsolt test with the single-session test reduce time, labor, and animals stress, but it may also improve the search for effective medications. Indeed, since psychostimulants reduce immobility in the Porsolt test, the specificity of the latter for selecting antidepressant drugs has been questioned (Petit-Demouliere et al., 2005). 2 Given the strong subjective component associated with the interpretation of behavioral tests, having an additional, preferably objective, assay would be useful. The combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test can reveal the dysregulation of the stress hormone axis in depression (Watson et al., 2006). Indeed, in animals with chronic epilepsy, DEX/ CRH test is consistently positive (Mazarati et al., 2009). The test is objective, inexpensive, and quick. In addition, the positive DEX/CRH test may serve as an independent disease biomarker, thereby addressing another important issue discussed by Brooks-Kayal et al. (2013).