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.
Highlights
The estimated lifetime prevalence of major depressive disorder (MDD) in Europe is 12.8% [1]
Wistar Kyoto (WKY) Rats Show Anxiety-Like Behavior, Anhedonia, Depressive-Like Behavior, and Working Memory Deficits Compared to Sprague Dawley (SD) Rats
Anxiety-like behavior was assessed in a novel environment open field test (Figures 1A–C), the female urine sniffing test (FUST) coupled to Ultrasonic vocalizations (USVs) recording was used to examine hedonic behavior (Figures 1D,E) and nonevoked USVs were recorded in the home cage of pair housed rats (Figure 1F)
Summary
The estimated lifetime prevalence of major depressive disorder (MDD) in Europe is 12.8% [1]. The majority of individuals diagnosed with MDD seek treatment [2] and the estimated European 12-month prevalence of antidepressant use is 7.2% [3]. Most antidepressant drugs on the market, including selective serotonin reuptake inhibitors (SSRIs), target monoamine neurotransmission and often take weeks or months to demonstrate a therapeutic effect [4]. A single sub-anesthetic dose of the non-competitive Nmethyl-D-aspartate (NMDA) receptor antagonist ketamine produces rapid (within hours) and long lasting (up to 7 days) antidepressant effects in TRD patients [6]. The growing clinical and preclinical evidence of ketamine efficacy in mood disorders [8], its widespread clinical utility may be limited by abuse potential [9] and side-effects, including dissociation, cognitive impairment and psychosis [10, 11]. The identification of translational assays to model the effects of ketamine preclinically are required to advance this drug discovery process
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