Oral dyskinesias and morphological changes in rat striatum during long-term haloperidol administration.
BACKGROUND
Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to increased glutamate release within the striatum. This may lead to excitotoxic degeneration and, as a consequence, persistent motor side effects.


OBJECTIVE
To investigate whether alterations in glutamatergic synapses within the striatum are associated with the development of neuroleptic-induced oral dyskinesia.


METHODS
Haloperidol was administered for 20 weeks, and rats with high and low levels of vacuous chewing movements (VCM) were analyzed for morphological changes with electron microscopy at three time points.


RESULTS
At week 8, the high VCM rats had a larger nerve terminal area and lower density of nerve terminal glutamate immunoreactivity than the other groups. After 18 weeks of treatment, the nerve terminal area was increased relative to controls in both the high and low VCM groups. After discontinuation of treatment, there were no significant morphological differences between the groups, but the level of VCM was still significantly increased in the high VCM group.


CONCLUSIONS
These results show that striatal glutamatergic transmission is affected during haloperidol treatment and the nerve terminal area and the density of nerve terminal glutamate immunoreactivity are important in determining the VCM response to haloperidol treatment. This indicates that increased glutamatergic synaptic activity in the striatum contributes to the development of human tardive dyskinesia.
Andreassen
O A
OA
Department of Physiology, University of Bergen, Bergen, Norway. ole.andreassen@ulleval.no
Meshul
C K
CK
Moore
C
C
Jørgensen
H A
HA
D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects* / Q000648:ultrastructure; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006220:Haloperidol / Q000633:toxicity*; D007150:Immunohistochemistry; D008409:Mastication / Q000187:drug effects; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D018698:Glutamic Acid; D006220:Haloperidol