Depression is one of the common prevalent forms of neuropsychiatric disorder and a leading cause for morbidity and mortality in the world. According to the World Health Organization, major depression is projected to become an important contributor to global public health problems by 2020. Despite the significant progress achieved in the pharmacotherapy of depression in recent years, limitations with current treatments still exist in terms of clinical efficacy, delayed onset of action, and associated side effects. In addition, patients with co-morbid depression and anxiety are not effectively treated with available antidepressants. One solution could be to target additional brain receptors and associated neuronal mechanisms in preclinical models for better understanding of the specific aspects of this unique type of depression. Consequently, the novel treatments could be used against co-morbid depression. Emerging evidence suggests that the Wistar Kyoto (WKY) rat strain is a unique preclinical model for neuropsychiatric dysfunction. Thus, the neurobiology of its phenotype could provide critical understanding of major depression and anxiety that leads to new therapeutics. Previous research indicates that the k-opioid receptor (KOR) system has been implicated in depression, and KOR antagonists have been investigated as potential antidepressants. In the present study, Carr and colleagues have proposed the WKY rat strain as a putative genetic model of co-morbid depression and anxiety. Using preclinical testing methods, the authors clearly demonstrated selective antidepressant efficacy of KOR antagonists (nor-binaltorphimine and DIPPA) in WKY rats compared to other rat strains. Furthermore, brain regions such as nucleus accumbens and piriform cortex as sites of action for KOR antagonists for antidepressant efficacy have been identified using c-fos expression, a marker for neuronal activation. Additionally, application of nor-binaltorphimine into the piriform cortex produced antidepressant-like effects in WKY rats, highlighting this brain region in the antidepressant-like effects to KOR antagonists. Overall, these observations convincingly support the use of WKY rat as a model of mood disorders involving KOR hyperactivity, and provide behavioral and biochemical evidence that KOR antagonists could be developed as novel antidepressants. Nevertheless, additional studies should add more information to address whether the KOR system is involved in the anxiogenic component of the WKY phenotype. Thus, genetic animal models and associated brain targets that display a unique neurobiological profile can be investigated to advance the development of effective treatments for co-morbid depression and anxiety in upcoming years.