Morphological Changes in Direct Pathway Striatal Neurons in a Rat Model of Tardive Dyskinesia.

Abstract

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. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.