Neurochemical basis for the absence of overt "stereotyped" behaviors in rats with up-regulated striatal D2 dopamine receptors.
Because of substantial evidence for the hyperdopaminergic hypothesis of tardive dyskinesia (TD), animal models, especially rats, treated chronically with neuroleptics continue to be used to study this disorder. The rat model has been criticized because, unlike TD, in rats there is an apparent lack of spontaneous abnormal movements even when striatal D2 dopamine receptor (DAr) density is substantially increased. Our data suggest a mechanism by which rats suppress these abnormal movements normally associated with elevated DAr levels. We correlated neurochemical with behavioral changes using several animal models, including nonneuroleptic ones, which elicit varied levels of DAr upregulation. There was (as expected) a robust, significant, positive correlation between striatal DAr density and apomorphine-induced stereotypic behaviors. In contrast, there was a significant negative correlation between increased DAr density and synthesis capacity for striatal DA (Vmax for tyrosine hydroxylase). We conclude that this decrease in Vmax is a compensatory adjustment of the nigrostriatal DA tract for the increased DAr density induced in our animal models. Our data further suggest the generalization that an observed increase in receptor density doesn't necessarily predict a functional change (spontaneous behavior, neuropathology) because compensatory neural mechanisms exist. In TD these compensatory neural mechanisms may fail, leading to spontaneous behaviors.
Department of Pharmacology and Experimental Therapeutics, Loyola University, Stritch School of Medicine, Illinois.
J Z
JZ
Fields
G E
GE
Drucker
L
L
Wichlinski
J H
JH
Gordon
D000818:Animals; D014150:Antipsychotic Agents; D001058:Apomorphine; D003342:Corpus Striatum / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology; D007700:Kinetics; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013134:Spiperone; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine