Relevance of animal models to human tardive dyskinesia

Tardive dyskinesia (TD) is a disabling and potentially irreversible motor complication encompassing all persistent, abnormal, involuntary hyperkinetic movements occurring in the setting of chronic therapy with dopamine receptor-blocking agents, such as antipsychotic drugs and metoclopramide [1]. The resulting movement disorder is most often stereotyped in nature and typically involves the orobuccolingual musculature. As TD remains an elusive drug complication over 50 years since its initial description, it is not surprising that the treatment options available are non-specific and produce mixed results.Unfortunately, the early hope that second-generation (so-called atypical) antipsychotic drugs would afford a gradual disappearance of TD has been challenged by recent reports that one third of patients chronically exposed to antipsychotic drugs still develop TD [2-4]. The annual risk remains greater in older adults, particularly in those living with a dementing illness [5]. Severe forms of TD also develop with the new antipsychotic drugs [6]. The persistence of TD in the community, and the enlarging spectrum of conditions for which antipsychotic drugs are prescribed (e.g., bipolar disorder, refractory depression), make it urgent to develop a better understanding of this hyperkinetic movement disorder, as well as novel preventive and palliative approaches. The use of animal models is inescapable and irreplaceable in reaching that goal. The advances made since the levodopa-induced dyskinesia primate model was introduced in neuroscience 25 years ago well illustrate that point [7,8]. Before mechanistic considerations are addressed, any experimental movement disorder model must first reproduce the phenomenology of the human condition, a test the levodopa-induced dyskinesia primate model has unequivocally passed. The purposeless hyperkinetic movements should be reproducible, quantifiable, and easily distinguishable from normal movements. This personal review of rodent as we