Neurobiological Basis of Dyskinetic Effects Induced by Antipsychotics: the Contribution of Animal Models

Abstract

Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications. Currently, there is no satisfactory pharmacotherapy for TD, which represents a major limitation to therapy with classical antipsychotics. In order to develop or optimize therapies for TD, and to develop new APDs with lower indices of motor side effects, the pathology underlying TD must first be understood. The use of animal models has been used to further this objective. Here, we review different preparations that have been used to model TD and discuss the contribution of neuroimaging studies conducted in these models. Studies in animal models have lead to several hypotheses of TD pathology, although none has yet emerged as the ultimate underlying cause of this syndrome. We discuss alterations in functional indices, neuron and synapse morphology and changes in specific neurotransmitter systems that have been described in animal models of TD, and outline how these findings have contributed to our understanding of antipsychotic-induced dyskinesias. We conclude that several non-mutually exclusive theories of TD are supported by animal studies, including increases in oxidative stress leading to structural and functional changes in specific neurotransmitter systems. Elucidating the mechanisms underlying TD neuropathology partly through the use of animal models will lead to the development of APDs with superior side effect profiles or more effective therapies for TD.

Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials

“…This set the stage for a body of work that approached this question from a number of related directions. Loosely grouped under the framework of 'neurotoxicity' and not mutually exclusive, they have been more discretely categorized as representing at least three types of change in response to chronic AP exposure: morphological, neuroplastic and neurodegenerative (see Creed and Nobrega [69], for review). In the case of morphological/structural, there is a growing body of evidence indicating that CNS changes occur in response to ongoing AP exposure [70,71].…”

“…Neuroimaging has contributed substantially to this line of research in recent years, although: i) much of this work is not specific to TD; and ii) these findings must be interpreted in the context of aging and/or neuroprogressive changes proposed to be illness-related [72]. In respect to neuroplastic alterations (e.g., changes in synaptic proteins), results have been variable and few have been specifically associated with dyskinetic effects per se (e.g., vacuous chewing movements [VCMs] in rodent models) [69]. The body of evidence related to neurodegenerative changes best captures the connotations of 'neurotoxicity'; for example, loss of GABAergic striatal interneurons [73,74] aligns with several more popular hypotheses in terms of mechanism(s) of action implicating a neurodegenerative process.…”

“…The body of evidence related to neurodegenerative changes best captures the connotations of 'neurotoxicity'; for example, loss of GABAergic striatal interneurons [73,74] aligns with several more popular hypotheses in terms of mechanism(s) of action implicating a neurodegenerative process. This would include the free radical/oxidative stress model as well as the glutamatergic 'excitotoxicity hypothesis' [18,69,75,76]. In both cases, the models are premised on AP-related neuronal damage as a function of ongoing exposure.…”

“…The neurotoxicity model associated with ongoing AP exposure also sets the stage for work involving antioxidants, with ample evidence that AP administration is Emerging drugs for antipsychotic-induced TD Expert Opin. Emerging Drugs (2015) 20(3) associated with multiple changes in the CNS [69]. Complicating this story somewhat is the growing focus on neuroinflammation as an integral part of illnesses like schizophrenia and Parkinson's disease [133,134], suggesting that documented CNS changes are not just a function of AP exposure.…”