Antidepressant effects of ketamine on depression-related phenotypes and dopamine dysfunction in rodent models of stress

Depression, the most prevalent psychiatric disorder, is characterized by increased negative affect (i.e. depressed mood) and reduced positive affect (i.e. anhedonia). Stress is a risk factor for depression in humans, and animal models of chronic stress are typically used to study neurobehavioral alterations relevant to depression. Common behavioral outcomes in rodent models of chronic stress include anhedonia, social dysfunction and behavioral despair. For example, chronically stressed rodents exhibit reduced reward preference, as measured by a loss of preference for sucrose solutions and time spent interacting with a novel conspecific, while also exhibiting less time struggling against inescapable stressors (e.g. forced swim, tail suspension). In both humans and rodents, anhedonia is associated with dysfunction of the dopamine (DA) system. Unlike traditional antidepressants, which are limited by inadequate efficacy and delayed therapeutic response, acute ketamine administration rapidly alleviates depressive symptoms in humans and reverses stress-induced changes in animal models. These effects are partially mediated via actions on the DA system. This review summarizes the clinical effects of ketamine, the neurobiological underpinnings of depression with a focus on DA dysfunction, as well as antidepressant effects of ketamine on depression-related endophenotypes (i.e. anhedonia, despair) and ventral tegmental area (VTA) activity in rodent models of repeated stress. Moreover, we discuss evidence regarding sex differences in ketamine's antidepressant effects, wherein females appear to be more sensitive to lower dose ketamine, as well as novel findings suggesting that ketamine has prophylactic effects with regard to protection against the neurobehavioral impact of future stressors.