The Antidepressant-Like Effects of a Clinically Relevant Dose of Ketamine Are Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression

Abstract

Major depressive disorder (MDD) is the leading cause of disability worldwide. The majority of antidepressant drugs require several weeks or months of treatment to demonstrate efficacy and a subset of patients are resistant to such interventions. Ketamine demonstrates rapid and long-lasting antidepressant effects in treatment resistant patients; however, side effects may limit its widespread clinical utility. The pharmaceutical industry is engaged in developing novel rapid-acting antidepressant drugs and the establishment of clinically relevant assays are needed to advance this process. Wistar Kyoto (WKY) rats are a valuable model of many of the characteristics of MDD and their resistance to selective serotonin reuptake inhibitors (SSRIs) in several behavioral paradigms emulates treatment resistance in clinical populations. Here, we confirmed the depressive-like phenotype of WKY rats in comparison to Sprague Dawley rats, characterized by increased immobility in the forced swim test, decreased locomotor activity and entries to the centre in the open field test, anhedonia in the female urine sniffing test and working memory deficits in the delayed non-match to position task. Single subcutaneous administration of 5 mg/kg ketamine in WKY rats mirrored the plasma exposure produced by the antidepressant dose in the clinic and rescued depressive-like behaviors. The same dose induced transient side effects, including decreased locomotor activity and reduced positive affect-associated vocalizations. Furthermore, ketamine acutely impaired working memory but induced pro-cognitive effects at a later time point. These data confirm the WKY rat as a preclinical model of depression. Ketamine's efficacy in recovering this depressive-like phenotype while inducing transient dissociative-like effects supports this as a translational model suitable for investigating novel antidepressant drugs.

Traxoprodil Produces Antidepressant-Like Behaviors in Chronic Unpredictable Mild Stress Mice through BDNF/ERK/CREB and AKT/FOXO/Bim Signaling Pathway

“…However, additional studies are warranted to explore the antidepressant effects of traxoprodil in different concentrations and durations of treatment. The FST and TST, also known as behavioral despair models, have become the most widely used models for assessing the effects of antidepressants due to strong reliability, high predictive efficacy, and easy operation [31,32]. Consistent with previous literature [33,34], our study showed that immobility time during the FST and TST was prolonged in CUMS mice compared to control mice.…”

The Wistar Kyoto Rat: A Model of Depression Traits

“…In addition, electroconvulsive stimulation, the equivalent of electroconvulsive treatment in humans, does reduce WKY immobility in the FST without increasing general activity measures [ 245 , 246 ]. Other therapies that reduce anhedonia in stressed WKYs include deep brain stimulation [ 234 , 247 , 248 ] and low doses of ketamine [ 234 , 249 - 251 ], which have shown similar clinical efficacy in treating pharmacoresistant MDD patients [ 252 , 253 ]. We do not know if these treatments in humans generate active coping or reduce passive coping with stress, but we know that they are effective in reducing depressive symptoms.…”

Mangiferin Alleviates Postpartum Depression–Like Behaviors by Inhibiting MAPK Signaling in Microglia

“…As a common but severe mental health disorder, PPD poses a serious global burden worldwide. Multiple animal models of PPD have been established to explore its pathogenesis, including stress-induced (Boccia et al, 2007;Haim et al, 2016), HSPinduced (Stoffel and Craft, 2004;Schiller et al, 2013), and transgenic animal models (Tillmann et al, 2019;McDonnell et al, 2020). Among these, the HSP-induced model is commonly used due to its advantages such as good reproducibility and easier procedure.…”