Role of the mesolimbic dopamine pathway in the antidepressant effects of ketamine

Depression is a complex and highly heterogeneous disorder which diagnosis is based on an exceedingly variable set of clinical symptoms. Current treatments focus almost exclusively on the manipulation of monoamine neurotransmitter systems, but despite considerable efforts, these remain inadequate for a significant pro-portion of those afflicted by the disorder. The emergence of racemic (R, S)-ketamine as a fast-acting antidepressant has provided an exciting new path for the study of major depressive disorder (MDD) and the search for better therapeutics for its treatment. Previous work suggested that ketamine's mechanism of action is primarily mediated via blockaded of N-methyl-D-aspartate (NMDA) receptors, however, this is an area of active research and clinical and preclinical evidence now indicate that ketamine acts on multiple systems. The last couple of decades have cemented the mesolimbic dopamine reward pathway's involvement in the pathogenesis of MDD and related mood disorders. Exposure to negative stress dysregulates dopamine neuronal activity disrupting reward and motivational processes resulting in anhe-donia (lack of pleasure), a hallmark symptom of depression. Although the mechanism(s) underlying ketamine's antidepressant activity continue to be elucidated, current evidence indicate that its therapeutic effects are mediated, at least in part, via long-lasting synaptic changes and subsequent molecular adaptations in brain regions within the mesolimbic dopamine system. Notwithstanding, ketamine is a drug of abuse, and this liability may pose limitations for long term use as an antidepressant. This review outlines the current knowledge of ketamine's actions within the mesolimbic dopamine system and its abuse potential.This article is part of the Special Issue on 'Ketamine and its Metabolites'.