Chapter title |
Lifelong Rodent Model of Tardive Dyskinesia—Persistence After Antipsychotic Drug Withdrawal
|
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Chapter number | 395 |
Book title |
Neurotoxin Modeling of Brain Disorders — Life-long Outcomes in Behavioral Teratology
|
Published in |
Current topics in behavioral neurosciences, January 2015
|
DOI | 10.1007/7854_2015_395 |
Pubmed ID | |
Book ISBNs |
978-3-31-934134-7, 978-3-31-934136-1
|
Authors |
Richard M. Kostrzewa, Ryszard Brus, Kostrzewa, Richard M., Brus, Ryszard |
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) D2 receptors (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persists lifelong after haloperidol withdrawal, but is not associated with an increased D2-R number in the haloperidol-withdrawn phase.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 Testing during the haloperidol-withdrawn phase in n6-OHDA rats displaying TD reveals that receptor agonists and antagonists of a host of neuronal phenotypic classes have virtually no effect on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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 18 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Doctoral Student | 3 | 17% |
Student > Master | 2 | 11% |
Librarian | 1 | 6% |
Student > Bachelor | 1 | 6% |
Other | 1 | 6% |
Other | 2 | 11% |
Unknown | 8 | 44% |
Readers by discipline | Count | As % |
---|---|---|
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 11% |
Nursing and Health Professions | 2 | 11% |
Biochemistry, Genetics and Molecular Biology | 1 | 6% |
Psychology | 1 | 6% |
Medicine and Dentistry | 1 | 6% |
Other | 3 | 17% |
Unknown | 8 | 44% |