1. Acute administration of haloperidol induces apoptosis of neurones in the striatum and substantia nigra in the rat
- Author
-
Ian J. Mitchell, A.C Cooper, A.J Cooper, and M.R Griffiths
- Subjects
Male ,Dyskinesia, Drug-Induced ,medicine.medical_specialty ,Central nervous system ,Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate ,Apoptosis ,Substantia nigra ,Striatum ,Tardive dyskinesia ,Drug Administration Schedule ,Avian Proteins ,Rats, Sprague-Dawley ,Antigens, CD ,Antigens, Neoplasm ,Internal medicine ,Neural Pathways ,Basal ganglia ,In Situ Nick-End Labeling ,Haloperidol ,medicine ,Animals ,Neurons ,Membrane Glycoproteins ,Behavior, Animal ,Dose-Response Relationship, Drug ,business.industry ,General Neuroscience ,Blood Proteins ,medicine.disease ,Immunohistochemistry ,Corpus Striatum ,Rats ,Substantia Nigra ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Dyskinesia ,Antigens, Surface ,Nerve Degeneration ,Basigin ,Dopamine Antagonists ,GABAergic ,medicine.symptom ,business ,Neuroscience ,medicine.drug - Abstract
Chronic administration of typical neuroleptics is associated with tardive dyskinesia in some patients. This dyskinetic syndrome has been associated with loss of GABAergic markers in the basal ganglia but the cause of these GABAergic depletions remains uncertain. Haloperidol, a commonly prescribed typical neuroleptic, is known to be toxic in vitro , possibly as a consequence of its conversion to pyridinium-based metabolites and potentially by raising glutamate-mediated transmission. We report here that the in vivo , acute administration of a large dose of haloperidol resulted in a microglial response indicative of neuronal damage. This was accompanied by an increase in the number of apoptotic cells in the striatum (especially in the dorsomedial caudate putamen) and in the substantia nigra pars reticulata. These apoptotic cells were characterised by the stereotaxic injection of a retrograde neuroanatomical tracer into the projection targets of the striatum and substantia nigra pars reticulata prior to the systemic injection of haloperidol. This procedure confirmed that the dying cells were neurones and demonstrated that within the striatum the majority were striatopallidal neurones though relatively high levels of apoptotic striatoentopeduncular neurones were also seen. The possibility that chronic administration of haloperidol could induce cumulative neuronal loss in the substantia nigra pars reticulata and thereby induce the pathological changes which lead to tardive dyskinesia is discussed.
- Published
- 2002