title: Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia?
abstract: Tardive dyskinesia is a serious motor side effect of long-term treatment with neuroleptics, with an unknown pathophysiologic basis. Brain damage and aging are prominent risk-factors, and together with the persistent character of the disorder, it is likely that long-lasting neuronal changes are involved in the pathogenesis. It has been hypothesized that striatal neurodegeneration caused by excitotoxic mechanisms and oxidative stress may play an important role in the development of the disorder, and the scope of the present work is to review the evidence supporting this hypothesis. The rat model of tardive dyskinesia has been used extensively in the field, and the usefulness of this model will be discussed. Neuroleptics are able to induce oxidative stress in vitro and increase striatal glutamatergic activity in rats, which may lead to toxic effects in the striatum. Drugs that block excitotoxicity inhibit the development of persistent oral dyskinesia in the rat model, and impaired energy metabolism leads to increased frequency of oral dyskinesia. There are also signs of altered striatal histology in rats with high frequency of oral dyskinesia. Furthermore, markers of increased oxidative stress and glutamatergic neurotransmission have been found in the cerebrospinal fluid of patients with tardive dyskinesia. In conclusion, several lines of evidence implicate neurotoxic events in the development of neuroleptic induced tardive dyskinesia.
authors.affiliation: Department of Psychiatry, Sandviken Hospital, University of Bergen, Bergen, Norway. andreass@helix.mgh.harvard.edu
authors.forename: O A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: H A
authors.initials: HA
authors.lastname: Jørgensen
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*; D006801:Humans; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D009498:Neurotoxins / Q000009:adverse effects*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats
chemical_list: D014150:Antipsychotic Agents; D009498:Neurotoxins