Analysis reveals altered axon terminals in direct pathway neurons in rats treated with haloperidol, indicating potential mechanisms for tardive dyskinesia.
Background Tardive dyskinesia (TD) and drug‐induced parkinsonism (DIP) arise from prolonged dopamine antagonist use. Although D2 receptor hypersensitivity in the indirect pathway is a proposed mechanism, the role of the direct pathway remains unclear. Objectives To investigate morphological changes in the direct pathway striatal neurons' axon terminals in a rat model of haloperidol‐induced TD and DIP. Methods Male Wistar rats received haloperidol decanoate or placebo over 6 months. Behavioral tests assessed TD‐ and DIP‐like symptoms. Axon terminals forming synapses on dendrites in the internal (GPi) and external (GPe) segments of the globus pallidus were analyzed using electron and immunoelectron microscopy. Results Haloperidol‐treated rats exhibited both TD‐ and DIP‐like behaviors. Vesicular gamma‐aminobutyric acid (GABA) transporter (VGAT)‐positive terminals were selectively enlarged in the GPi, and substance P colocalization indicated a direct pathway origin. Conclusions Structural alterations in direct pathway nerve terminals may contribute to TD, challenging conventional models that focus solely on the indirect pathway.
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Hikichi et al. (2025) studied this question.
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