title: Lifelong Rodent Model of Tardive Dyskinesia-Persistence After Antipsychotic Drug Withdrawal.
abstract: Tardive dyskinesia (TD), first appearing in humans after introduction of the phenothiazine class of antipsychotics in the 1950s, is now recognized as an abnormality resulting predominately by long-term block of dopamine (DA) D2receptors (R). TD is thus reproduced in primates and rodents by chronic administration of D2-R antagonists. Through a series of studies predominately since the 1980s, it has been shown in rodent modeling of TD that when haloperidol or other D2-R antagonist is added to drinking water, rats develop spontaneous oral dyskinesias, vacuous chewing movements (VCMs), after ~3 months, and this TD is associated with an increase in the number of striatal D2-R. This TD persists for the duration of haloperidol administration and another ~2 months after haloperidol withdrawal. By neonatally lesioning dopaminergic nerves in brain in neonatal rats with 6-hydroxydopamine (6-OHDA), it has been found that TD develops sooner, at ~2 months, and also is accompanied by a much higher number of VCMs in these haloperidol-treated lesioned rats, and the TD persists lifelong after haloperidol withdrawal, but is not associated with an increased D2-R number in the haloperidol-withdrawn phase. TD apparently is related in part to supersensitization of both D1-R and serotoninergic 5-HT2-R, which is also a typical outcome of neonatal 6-OHDA (n6-OHDA) lesioning. Testing during the haloperidol-withdrawn phase in n6-OHDA rats displaying TD reveals that receptor agonists and antagonists of a host of neuronal phenotypic classes have virtually no effect on spontaneous VCM number, except for 5-HT2-R antagonists which acutely abate the incidence of VCMs in part. Extrapolating to human TD, it appears that (1) 5-HT2-R supersensitization is the crucial alteration accounting for persistence of TD, (2) dopaminergic-perhaps age-related partial denervation-is a risk factor for the development of TD, and (3) 5-HT2-R antagonists have the therapeutic potential to alleviate TD, particularly if/when an antipsychotic D2-R blocker is withdrawn.
authors.affiliation: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, PO Box 70577, Johnson City, TN, 37614, USA. kostrzew@etsu.edu.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Kostrzewa
authors.affiliation: Department of Nurse, High School of Strategic Planning, Koscielna 6, 41-303, Dabrowa Gornicza, Poland.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Brus
keywords: 5-HT2-Receptor; 6-OHDA; 6-hydroxydopamine; Antipsychotic; Dopamine; Haloperidol; Oral dyskinesia; Receptor supersensitivity; Serotonin; Tardive dyskinesia; Vacuous chewing movements