Can the supersensitivity of rodents to dopamine be regarded as a model of tardive dyskinesia?
1. The paper presents arguments derived from both, clinical work and animal experiments, for or against the traditional hypothesis suggesting that tardive dyskinesia (TD) is caused by supersensitivity to dopamine. The main aim of this study was to answer the question posed in the title - whether the supersensitivity to dopamine evoked in rodents by neuroleptics can be regarded as an adequate pharmacological model of TD. 2. The data presented here prove that chronic administration of neuroleptics to schizophrenic patients cannot be the only factor inducing TD; furthermore, symptoms similar or identical to those of TD are also observed in the course of other disorders, not connected with neuroleptics, e.g. aging or schizophrenia itself. 3. Clinical data offer no clear evidence for the existence of a direct cause-effect relationship between super-sensitivity to dopamine and occurrence of TD. 4. The role of brain degeneration, caused by different factors but in particular by the process of aging, in the pathogenesis of dyskinetic disorders, including TD, has been stressed. 5. Pharmacological and biochemical data show that chronic administration of classic neuroleptics to animals induces an increase in the density of dopamine D-2 receptors (Bmax). It seems that this receptor-mediated supersensitivity may concern both the postsynaptic and the presynaptic D-2 dopamine receptors. On the other hand, it is not clear enough whether a dopamine D-1 receptor-mediated supersensitivity might also be a causal factor of TD. 6. The analysis in animals, of biochemical and pharmacological effects of neuroleptics which do not induce TD showed that in some situations these drugs may also evoke the receptor-mediated supersensitivity concerning dopamine D-2 receptors. 7. The method of a prolonged (approx. 1 year) oral administration of neuroleptics seems to differentiate those which induce TD from those which do not, at least regarding the induction of an increase of Bmax for butyrophenone neuroleptics and an increase of apomorphine-induced stereotypy, however, some exceptions are noted. 8. The above analysis of clinical and experimental data suggests that the supersensitivity to dopamine in rats treated chronically with neuroleptics cannot be accepted as a model which reflects the etiopathogenesis of TD. Neither a positive nor a negative result obtained in this test is reliable enough, and either depends on the tested parameters (apomorphine stereotypy and [3H]spiperon binding seem to be the most reliable), route of neuroleptic administration, duration of treatment and, probably, a number of other, still unknown factors.(ABSTRACT TRUNCATED AT 400 WORDS)
Wolfarth
S
S
Department of Neuropsychopharmacology, Polish Academy of Sciences, Krakow, Poland.
Ossowska
K
K
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D006801:Humans
D004298:Dopamine